Hydroxymethylcyclohexylamines

ABSTRACT

The invention relates to compounds which have an affinity for the μ opioid receptor and the ORL1 receptor, processes for the preparation thereof, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.

This application is a Continuation of PCT/EP2009/002184, filed Mar. 25,2009, which claims foreign priority benefit under 35 U.S.C. §119 of theEuropean Patent Application No. 08005809.2 filed Mar. 27, 2008.

The present invention relates to hydroxymethylcyclohexylamines whichhave an affinity for the μ opioid receptor and the ORL1 receptor,processes for the preparation thereof, medicaments containing thesecompounds and the use of these compounds for the preparation ofmedicaments.

Cyclohexane derivatives which have an affinity for the μ opioid receptorand the ORL1 receptor are known in the prior art. In this connection,reference may be made by way of example, in the full scope, toWO2002/090317, WO2002/90330, WO2003/008370, WO2003/008731,WO2003/080557, WO2004/043899, WO2004/043900, WO2004/043902,WO2004/043909, WO2004/043949, WO2004/043967, WO2005/063769,WO2005/066183, WO2005/110970, WO2005/110971, WO2005/110973,WO2005/110974, WO2005/110975, WO2005/110976, WO2005/110977,WO2006/018184, WO2006/108565, WO2007/079927, WO2007/079928,WO2007/079930, WO2007/079931, WO2007/124903, WO2008/009415 andWO2008/009416.

However, the known compounds are not satisfactory in every respect.Thus, the known compounds sometimes show a not always optimum affinityfor the ORL1 receptor. In general, it can be assumed that as theaffinity of a compound for the ORL1 receptor increases, the doserequired to bring about the same pharmacological action decreases. Thelower the dose required, however, the lower also the probability of theoccurrence of undesirable side effects.

Furthermore, in suitable binding assays the known compounds sometimesshow a certain affinity for the hERG ion channel, for the L-type calciumion channel (phenylalkylamine, benzothiazepine, hydropyridine bindingsites) or for the sodium channel in the BTX assay (batrachotoxin), whichcan in each case be interpreted as an indication of cardiovascular sideeffects. Numerous of the known compounds furthermore show only a lowsolubility in aqueous media, which can have an adverse effect, interalia, on the bioavailability. The chemical stability of the knowncompounds moreover is often only inadequate. Thus, the compoundssometimes do not show an adequate pH, UV or oxidation stability, whichcan have an adverse effect, inter alia, on the storage stability andalso on the oral bioavailability. The known compounds furthermore insome cases have an unfavourable PK/PD (pharmacokinetic/pharmacodynamic)profile, which can manifest itself e.g. in too long a duration ofaction.

The metabolic stability of the known compounds also appears to be inneed of improvement. An improved metabolic stability can indicate anincreased bioavailability. A weak or non-existent interaction withtransporter molecules involved in the uptake and excretion of drugs isalso to be evaluated as an indication of an improved bioavailability andat best low drug interactions.

Furthermore, the interactions with the enzymes involved in the breakdownand excretion of enzymes should be as low as possible, since such testresults likewise indicate that at best low drug interactions or none atall are to be expected.

There is a need for further compounds which bind to the ORL1 receptor.The compounds should as far as possible show at least a comparable,preferably a higher affinity for the ORL1 receptor. Additional bindingto other receptors (e.g. μ opioid receptor, δ opioid receptor) and theadditional antagonistic action on other receptors (e.g. B1R receptor)can bring additional advantages.

The compounds moreover should as far as possible have a comparable, butpreferably a better solubility in aqueous media.

The invention is based on the object of providing compounds which aresuitable for pharmaceutical purposes and have advantages over thecompounds of the prior art.

This object is achieved by the subject matter of the claims. It has beenfound, surprisingly, that substituted cyclohexane derivatives which havean affinity for the μ opioid receptor and the ORL1 receptor can beprepared.

The invention relates to compounds of the general formula (1)

wherein

-   Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently of    each other are chosen from the group consisting of —H, —F, —Cl, —Br,    —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀,    —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,    —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —S(═O)₁₋₂R₀,    —S(═O)₁₋₂OH, —S(═O)₁₋₂OR₀, —S(═O)₁₋₂NH₂, —S(═O)₁₋₂NHR₀ or    —S(═O)₁₋₂N(R₀)₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,    —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NH—C(═O)N(R₀)₂;    preferably in each case independently of each other are chosen from    the group consisting of —H, —F, —Cl, —CN and —C₁₋₈-aliphatic; or Y₁    and Y₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ together    represent ═O;-   R₀ in each case independently represents —C₁₋₈-aliphatic,    —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,    —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,    —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic,    —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl;-   R₁ and R₂ independently of each other represent —H or    —C₁₋₈-aliphatic, wherein R₁ and R₂ preferably do not both represent    —H; or R₁ and R₂ together form a ring and represent —(CH₂)₂₋₄;-   R₃ represents —R₀;-   R₄ represents —H, —F, —Cl, —Br, —I, —R₀, —C(═O)H, —C(═O)R₀,    —C(═O)OR₀, —CN, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀,    —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —NH₂,    —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,    —NHC(═O)NHR₀, —NHC(═O)—N(R₀)₂, —NO₂, —SH, —SR₀, —S(═O)₁₋₂R₀,    —S(═O)₁₋₂OH, —S(═O)₁₋₂OR₀, —S(═O)₁₋₂NH₂, —S(═O)₁₋₂NHR₀,    —S(═O)₁₋₂N(R₀)₂, —OS(═O)₁₋₂R₀, —OS(═O)₁₋₂OH, —OS(═O)₁₋₂OR₀,    —OS(═O)₁₋₂NH₂, —OS(═O)₁₋₂NHR₀ or —OS(═O)₁₋₂N(R₀)₂;-   R₅ represents —H, —R₀, —C(═O)H, —C(═O)R₀, —C(═O)OR₀, —CN, —C(═O)NH₂,    —C(═O)NHR₀ or —C(═O)N(R₀)₂;-   wherein-   “aliphatic” in each case is a branched or unbranched, saturated or    mono- or polyunsaturated, unsubstituted or mono- or polysubstituted,    aliphatic hydrocarbon radical;-   “cycloaliphatic” in each case is a saturated or mono- or    polyunsaturated, unsubstituted or mono- or polysubstituted,    alicyclic, mono- or multicyclic hydrocarbon radical, the number of    ring carbon atoms of which is preferably in the stated range (i.e.    “C₃₋₈-”cycloaliphatic preferably has 3, 4, 5, 6, 7 or 8 ring carbon    atoms);-   wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- or    polysubstituted” is understood as meaning substitution once or    several times of one or more hydrogen atoms, i.e. substitution once,    twice, three times or completely, by substituents chosen    independently of each other from the group consisting of —F, —Cl,    —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH,    —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H,    —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀,    —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,    —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)—NHR₀,    —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂;-   “aryl” in each case independently represents a carbocyclic ring    system having at least one aromatic ring, but without hetero atoms    in this ring, wherein the aryl radicals can optionally be fused with    further saturated, (partially) unsaturated or aromatic ring systems,    which in their turn can have one or more hetero ring atoms, in each    case independently of each other chosen from N, O and S, and wherein    each aryl radical can be unsubstituted or mono- or polysubstituted,    wherein the substituents on aryl can be identical or different and    can be in any desired and possible position of the aryl;-   “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic    radical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the    hetero atoms are identical or different and are nitrogen, oxygen or    sulfur and the heterocyclyl can be unsubstituted or mono- or    polysubstituted; wherein in the case of substitution on the    heterocyclyl the substituents can be identical or different and can    be in any desired and possible position of the heteroaryl; and    wherein the heterocyclyl can also be part of a bi- or polycyclic    system;-   wherein with respect to “aryl” and “heteroaryl”, “mono- or    polysubstituted” is understood as meaning substitution once or    several times of one or more hydrogen atoms of the ring system by    substituents chosen from the group consisting of —F, —Cl, —Br, —I,    —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀,    —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀,    —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH,    —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂,    —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂,    —NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂; wherein N ring    atoms optionally present can in each case be oxidized (N-oxide);-   in the form of an individual stereoisomer or mixture thereof, the    free compounds and/or their physiologically acceptable salts and/or    solvates.

Where various radicals are combined, for example R₁ and R₂, and whereradicals on substituents thereof are combined, such as e.g. —OR₀,—OC(═O)R₀, —OC(═O)NHR₀, a substituent, e.g. R₀, can assume differentmeanings for two or more radicals, for example —OR₀, —OC(═O)R₀,—OC(═O)NHR₀, within a substance.

The compounds according to the invention show good binding to the ORL1receptor and the μ opioid receptor.

In a preferred embodiment, the compounds according to the invention havea ratio of ORL1/μ affinity of at least 0.1. The ORL1/μ ratio is definedas 1/[K_(i(ORL1))/K_(i(μ))]. Particularly preferably, the ORL1/μ ratiois at least 0.2 or at least 0.5, more preferably at least 1.0 or atleast 2.0, still more preferably at least 3.0 or at least 4.0, mostpreferably at least 5.0 or at least 7.5, and in particular at least 10or at least 15. In a preferred embodiment the ORL1/μ ratio is in therange of from 0.1 to 30, more preferably 0.1 to 25.

In another preferred embodiment, the compounds according to theinvention have a ratio of ORL1/μ affinity of more than 30, morepreferably at least 50, still more preferably at least 100, mostpreferably at least 200 and in particular at least 300.

The compounds according to the invention preferably have a K_(i) valueon the μ opioid receptor of at most 500 nM, more preferably at most 100nM, still more preferably 50 nM, most preferably at most 10 nM and inparticular at most 1.0 nM.

Methods for determination of the K_(i) value on the μ opioid receptorare known to the person skilled in the art. The determination ispreferably carried out as described in connection with the examples.

The compounds according to the invention preferably have a K_(i) valueon the ORL1 receptor of at most 500 nM, more preferably at most 100 nM,still more preferably 50 nM, most preferably at most 10 nM and inparticular at most 1.0 nM.

Methods for determination of the K_(i) value on the ORL1 receptor areknown to the person skilled in the art. The determination is preferablycarried out as described in connection with the examples.

It has been found, surprisingly, that compounds with an affinity for theORL1 and μ opioid receptor in which the ratio of ORL1 to μ defined by1/[K_(i(ORL1))/K_(i(μ))] is in the range of from 0.1 to 30, preferablyfrom 0.1 to 25, have a pharmacological profile which has clearadvantages compared with the other opioid receptor ligands:

-   -   1. The compounds according to the invention show an activity in        acute pain models which is sometimes comparable to that of the        usual level 3 opioids. At the same time, however, they are        distinguished by a clearly better tolerability compared with        conventional μ opioids.    -   2. In contrast to the usual level 3 opioids, the compounds        according to the invention show a clearly higher activity in        mono- and polyneuropathy pain models, which is to be attributed        to a synergism of the ORL1 and μ opioid component.    -   3. In contrast to the usual level 3 opioids, the compounds        according to the invention show a substantial, preferably a        complete separation of antiallodynic or antihyperalgesic action        and antinociceptive effect in neuropathic animals.    -   4. In contrast to the usual level 3 opioids, the compounds        according to the invention show a clear intensification of        action against acute pain in animal models for chronic        inflammation pain (inter alia carrageenan- or CFA-induced        hyperalgesia, visceral inflammation pain).    -   5. In contrast to the usual level 3 opioids, side effects        typical of μ-opioids (inter alia respiratory depression,        opioid-induced hyperalgesia, physical dependency/withdrawal,        emotional dependency/addiction) are clearly reduced or        preferably are not to be observed with the compounds according        to the invention in the therapeutically active dose range.

On the basis of the reduced μ opioid side effects on the one hand andthe increased activity on chronic, preferably neuropathic pain on theother hand, the mixed ORL1/μ agonists are thus distinguished by clearlyincreased safety margins compared with pure μ opioids. This results in aclearly increased “therapeutic window” in the treatment of states ofpain, preferably chronic pain, still more preferably neuropathic pain.

Preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each caseindependently of each other are chosen from the group consisting of —H,—F, —Cl, —Br, —I, —CN, —NH₂, —NH—C₁₋₆-aliphatic,—NH—C₃₋₈-cycloaliphatic, —NH—C₁₋₆-aliphatic-OH, —N(C₁₋₆-aliphatic)₂,—N(C₃₋₈-cycloaliphatic)₂, —N(C₁₋₆-aliphatic-OH)₂, —NO₂,—NH—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —NH—C₁₋₆-aliphatic-aryl,—NH—C₁₋₆-aliphatic-heteroaryl, —NH-aryl, —NH-heteroaryl, —SH,—S—C₁₋₆-aliphatic, —S—C₃₋₈-cycloaliphatic,—S—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —S—C₁₋₆-aliphatic-aryl,—S—C₁₋₆-aliphatic-heteroaryl, —S-aryl, —S-heteroaryl, —OH,—O—C₁₋₆-aliphatic, —O—C₃₋₈-cycloaliphatic, —O—C₁₋₆-aliphatic-OH,—O—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —O—C₁₋₆-aliphatic-aryl,—O—C₁₋₆-aliphatic-heteroaryl, —O-aryl, —O-heteroaryl,—O—C(═O)C₁₋₆-aliphatic, —O—C(═O)C₃₋₈-cycloaliphatic,—O—C(═O)C₁₋₆-aliphatic-OH, —O—C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—O—C(═O)C₁₋₆-aliphatic-aryl, —O—C(═O)C₁₋₆-aliphatic-heteroaryl,—O—C(═O)aryl, —O—C(═O)heteroaryl, —C₁₋₆-aliphatic, —C₃₋₈-cycloaliphatic,—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-aryl,—C₁₋₆-aliphatic-heteroaryl, -aryl, -heteroaryl, —C(═O)C₁₋₆-aliphatic,—C(═O)C₃₋₈-cycloaliphatic, —C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—C(═O)C₁₋₆-aliphatic-aryl, —C(═O)C₁₋₆-aliphatic-heteroaryl, —C(═O)aryl,—C(═O)heteroaryl, —CO₂H, —CO₂—C₁₋₆-aliphatic, —CO₂—C₃₋₈-cycloaliphatic,—CO₂—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —CO₂—C₁₋₆-aliphatic-aryl,—CO₂—C₁₋₆-aliphatic-heteroaryl, —CO₂-aryl, —CO₂-heteroaryl; or Y₁ andY₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ together represent ═O.Preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each caseindependently of each other are chosen from the group consisting of —H,—F, —Cl, —Br, —I, —CN, —NH₂ and —OH.

In a preferred embodiment, one of the radicals Y₁, Y₁′, Y₂, Y₂′, Y₃,Y₃′, Y₄ and Y₄′ differs from —H and the remaining radicals represent —H.

Particularly preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ eachrepresent —H.

R₀ preferably in each case independently represents —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or—C₁₋₈-aliphatic-heteroaryl. In this context,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or—C₁₋₈-aliphatic-heteroaryl means that the radicals—C₃₋₁₂-cycloaliphatic, -aryl or -heteroaryl are in each case bonded viaa divalent —C₁₋₈-aliphatic-bridge. Preferred examples for—C₁₋₈-aliphatic-aryl are —CH₂—C₆H₅, —CH₂CH₂—C₆H₅, and —CH═CH—C₆H₅.

R₁ and R₂ independently of each other represent —H or —C₁₋₅-aliphatic,or the radicals R₁ and R₂ together form a ring and denote —(CH₂)₂—,—(CH₂)₃— or —(CH₂)₄—. Preferably, R₁ and R₂ independently of each otherrepresent —H, —CH₃ or —CH₂CH₃, or R₁ and R₂ together form a ring andrepresent —CH₂CH₂— or —CH₂CH₂CH₂—. Compounds wherein R₁ and R₂independently of each other represent —CH₃ or —H, wherein R₁ and R₂ donot simultaneously denote —H, are particularly preferred. In a preferredembodiment, R₁=R₂. In another preferred embodiment, R₁≠R₂. Preferably,R₁ and R₂ together with the nitrogen atom to which they are bonded formone of the following functional groups:

Preferably, R₃ represents —C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic, -aryl,-heteroaryl; or -aryl, -heteroaryl or —C₃₋₈-cycloaliphatic in each casebonded via a —C₁₋₃-aliphatic group.

Preferably, R₃ represents -ethyl, -propyl, -butyl, -pentyl, -hexyl,-heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -naphthyl, -anthracenyl,-thiophenyl, -benzothiophenyl, -furyl, -thienyl, -thiazolyl,-benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl,-pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, in each caseunsubstituted or mono- or polysubstituted; -cyclopentyl, -cyclohexyl,-phenyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothiophenyl, -furyl,-thienyl, -thiazolyl, -benzofuranyl, -benzodioxolanyl, -indolyl,-indanyl, -benzodioxanyl, -pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinylbonded via a saturated, unbranched —C₁₋₃-aliphatic group and in eachcase unsubstituted or mono- or polysubstituted.

More preferably, R₃ represents -ethyl, -propyl, -butyl, -pentyl, -hexyl,-heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl, -naphthyl,-anthracenyl, -thiophenyl, -benzothiophenyl, -furyl, -thienyl,thiazolyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl,-benzodioxanyl, -pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, in eachcase unsubstituted or mono- or polysubstituted; or —C₅₋₆-cycloaliphatic,-phenyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothiophenyl,pyridyl, -furyl, -thienyl, -thiazolyl, -benzofuranyl, -benzodioxolanyl,-indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyrimidyl, -triazolyl or-pyrazinyl bonded via a saturated, unbranched —C₁₋₃-aliphatic group andin each case unsubstituted or mono- or polysubstituted.

More preferably, R₃ represents -propyl, -butyl, -pentyl, -hexyl,-phenyl, -thiophenyl, -furyl, -thienyl, thiazolyl, -naphthyl, benzyl,-benzofuranyl, -indolyl, -indanyl, -benzodioxanyl, -benzodioxolanyl,-pyridyl, -pyrimidyl, -pyrazinyl, triazolyl or benzothiophenyl, in eachcase substituted or mono- or polysubstituted; or -phenyl, -furyl,-thienyl or -thiazolyl bonded via a saturated, unbranched—C₁₋₃-aliphatic group and in each case unsubstituted or mono- orpolysubstituted.

Still more preferably, R₃ represents -propyl, -butyl, -pentyl, -hexyl,-phenyl, -phenethyl, -thiophenyl, -pyridyl, -triazolyl, -benzothiophenylor -Benzyl, in each case substituted or unsubstituted, particularlypreferably -propyl, -3-methoxypropyl, -butyl, -pentyl, -hexyl, -phenyl,-3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -thienyl,-benzothiophenyl, -4-chlorobenzyl, -benzyl, -3-chlorobenzyl,-4-methylbenzyl, -2-chlorobenzyl, -4-fluorobenzyl, -3-methylbenzyl,-2-methylbenzyl, -3-fluorobenzyl, -2-fluorobenzyl,-1-methyl-1,2,4-triazolyl or -phenethyl.

Very particularly preferably, R₃ represents -butyl, -ethyl,-3-methoxypropyl, -benzothiophenyl, -phenyl, -3-methylphenyl,-3-fluorophenyl, -benzo[1,3]-dioxolyl, -benzyl,-1-methyl-1,2,4-triazolyl, -thienyl or -phenethyl.

Most preferably, R₃ represents -phenyl, -benzyl or -phenethyl, in eachcase unsubstituted or mono- or polysubstituted on the ring;—C₁₋₅-aliphatic, —C₄₋₆-cycloaliphatic, -pyridyl, -thienyl, -thiazolyl,-imidazolyl, -1,2,4-triazolyl or -benzimidazolyl, unsubstituted or mono-or polysubstituted.

Particularly preferably, R₃ represents -phenyl, -benzyl, -phenethyl,-thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4-triazolyl,-benzimidazolyl or -benzyl, unsubstituted or mono- or polysubstituted by—F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃,—OC₂H₅ or —N(CH₃)₂; -ethyl, -n-propyl, -2-propyl, -allyl, -n-butyl,-iso-butyl, -sec-butyl, -tert-butyl, -n-pentyl, -iso-pentyl,-neo-pentyl, -n-hexyl, -cyclopentyl or -cyclohexyl, in each caseunsubstituted or mono- or polysubstituted by —OH, —OCH₃ or —OC₂H₅,-thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4-triazolyl and-benzimidazolyl preferably being unsubstituted.

In a preferred embodiment, R₃ represents —C₁₋₆-aliphatic, -aryl(preferably -phenyl) or -heteroaryl (preferably -thienyl, -thiazolyl or-pyridyl), wherein -aryl and -heteroaryl are in each case unsubstitutedor mono- or polysubstituted by substituents independently of each otherchosen from —F, —Cl, —Br, —I, —CH₃, —OCH₃ and —OH.

Particularly preferably, R³ represents -phenyl, unsubstituted ormonosubstituted by —F, —Cl, —CN, —CH₃; -thienyl, -ethyl, -n-propyl or-n-butyl, unsubstituted or mono- or polysubstituted by —OCH₃, —OH or—OC₂H₅, in particular by —OCH₃.

Preferably, R₄ represents —H, —F, —Cl, —Br, —I, —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,—C₁₋₈-aliphatic-heteroaryl, —C(═O)H, —C(═O)—C₁₋₈-aliphatic,—C(═O)—C₃₋₁₂-cycloaliphatic, —C(═O)-aryl, —C(═O)-heteroaryl,—C(═O)—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C(═O)—C₁₋₈-aliphatic-aryl,—C(═O)—C₁₋₈-aliphatic-heteroaryl, —C(═O)O—C₁₋₈-aliphatic,—C(═O)O—C₃₋₁₂-cycloaliphatic, —C(═O)O-aryl, —C(═O)O-heteroaryl,—C(═O)O—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C(═O)O—C₁₋₈-aliphatic-aryl, —C(═O)O—C₁₋₈-aliphatic-heteroaryl, —CN,—C(═O)NH₂, —C(═O)—NH—C₁₋₈-aliphatic, —C(═O)NH—C₃₋₁₂-cycloaliphatic,—C(═O)NH-aryl, —C(═O)NH-heteroaryl,—C(═O)—NH—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C(═O)NH—C₁₋₈-aliphatic-aryl, —C(═O)NH—C₁₋₈-aliphatic-heteroaryl,—C(═O)N(C₁₋₈-aliphatic)₂, —C(═O)N(C₃₋₁₂-cycloaliphatic)₂,—C(═O)N(aryl)₂, —C(═O)N-(heteroaryl)₂,—C(═O)N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—C(═O)N(C₁₋₈-aliphatic-aryl)₂, —C(═O)—N(C₁₋₈-aliphatic-heteroaryl)₂,—OH, —OC₁₋₈-aliphatic, —OC₃₋₁₂-cycloaliphatic, -Oaryl, -Oheteroaryl,—OC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —OC₁₋₈-aliphatic-aryl,—OC₁₋₈-aliphatic-heteroaryl, —OC(═O)H, —OC(═O)—C₁₋₈-aliphatic,—OC(═O)—C₃₋₁₂-cycloaliphatic, —OC(═O)-aryl, —OC(═O)-heteroaryl,—OC(═O)—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OC(═O)—C₁₋₈-aliphatic-aryl, —OC(═O)—C₁₋₈-aliphatic-heteroaryl,—OC(═O)O—C₁₋₈-aliphatic, —OC(═O)O—C₃₋₁₂-cycloaliphatic, —OC(═O)O-aryl,—OC(═O)—O-heteroaryl, —OC(═O)O—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OC(═O)O—C₁₋₈-aliphatic-aryl, —OC(═O)—O—C₁₋₈-aliphatic-heteroaryl,—OC(═O)NH—C₁₋₈-aliphatic, —OC(═O)NH—C₃₋₁₂-cycloaliphatic,—OC(═O)NH-aryl, —OC(═O)NH-heteroaryl,—OC(═O)NH—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OC(═O)NH—C₁₋₈-aliphatic-aryl, —OC(═O)NH—C₁₋₈-aliphatic-heteroaryl,—OC(═O)N(C₁₋₈-aliphatic)₂, —OC(═O)N(C₃₋₁₂-cycloaliphatic)₂,—OC(═O)N(aryl)₂, —OC(═O)—N(heteroaryl)₂,—OC(═O)N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—OC(═O)N(C₁₋₈-aliphatic-aryl)₂, —OC(═O)N(C₁₋₈-aliphatic-heteroaryl)₂,—NH₂, —NO₂, —NH—C₁₋₈-aliphatic, —NH—C₃₋₁₂-cycloaliphatic, —NH-aryl,—NH-heteroaryl, —NH—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—NH—C₁₋₈-aliphatic-aryl, —NH—C₁₋₈-aliphatic-heteroaryl,—N(C₁₋₈-aliphatic)₂, —N(C₃₋₁₂-cycloaliphatic)₂, —N(aryl)₂,—N(heteroaryl)₂, —N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—N(C₁₋₈-aliphatic-aryl)₂, —N(C₁₋₈-aliphatic-heteroaryl)₂,—NHC(═O)—C₁₋₈-aliphatic, —NHC(═O)—C₃₋₁₂-cycloaliphatic, —NHC(═O)-aryl,—NHC(═O)-heteroaryl, —NHC(═O)—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—NHC(═O)—C₁₋₈-aliphatic-aryl, —NHC(═O)—C₁₋₈-aliphatic-heteroaryl,—NHC(═O)O—C₁₋₈-aliphatic, —NHC(═O)O—C₃₋₁₂-cycloaliphatic,—NHC(═O)O-aryl, —NHC(═O)O-heteroaryl,—NHC(═O)O—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—NHC(═O)O—C₁₋₈-aliphatic-aryl, —NHC(═O)O—C₁₋₈-aliphatic-heteroaryl,—NHC(═O)NH—C₁₋₈-aliphatic, —NHC(═O)NH—C₃₋₁₂-cycloaliphatic,—NHC(═O)NH-aryl, —NHC(═O)—NH-heteroaryl,—NHC(═O)NH—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—NHC(═O)NH—C₁₋₈-aliphatic-aryl, —NHC(═O)NH—C₁₋₈-aliphatic-heteroaryl,—NHC(═O)N(C₁₋₈-aliphatic)₂, —NHC(═O)N(C₃₋₁₂-cycloaliphatic)₂,—NHC(═O)N(aryl)₂, —NHC(═O)—N(heteroaryl)₂,—NHC(═O)—N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—NHC(═O)N(C₁₋₈-aliphatic-aryl)₂, —NHC(═O)N(C₁₋₈-aliphatic-heteroaryl)₂,—SH, —SC₁₋₈-aliphatic, —SC₃₋₁₂-cycloaliphatic, -Saryl, -Sheteroaryl,—SC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —SC₁₋₈-aliphatic-aryl,—SC₁₋₈-aliphatic-heteroaryl, —S(═O)₁₋₂C₁₋₈-aliphatic,—S(═O)₁₋₂C₃₋₁₂-cycloaliphatic, —S(═O)₁₋₂aryl, —S(═O)₁₋₂heteroaryl,—S(═O)₁₋₂C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—S(═O)₁₋₂C₁₋₈-aliphatic-aryl, —S(═O)₁₋₂C₁₋₈-aliphatic-heteroaryl,—S(═O)₁₋₂OH, —S(═O)₁₋₂OC₁₋₈-aliphatic, —S(═O)₁₋₂OC₃₋₁₂-cycloaliphatic,—S(═O)₁₋₂Oaryl, —S(═O)₁₋₂Oheteroaryl,—S(═O)₁₋₂OC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—S(═O)₁₋₂OC₁₋₈-aliphatic-aryl, —S(═O)₁₋₂OC₁₋₈-aliphatic-heteroaryl,—S(═O)₁₋₂NH₂, —S(═O)₁₋₂NHC₁₋₈-aliphatic,—S(═O)₁₋₂NHC₃₋₁₂-cycloaliphatic, —S(═O)₁₋₂NHaryl, —S(═O)₁₋₂NHheteroaryl,—S(═O)₁₋₂NHC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—S(═O)₁₋₂NHC₁₋₈-aliphatic-aryl, —S(═O)₁₋₂NHC₁₋₈-aliphatic-heteroaryl,—S(═O)₁₋₂N(C₁₋₈-aliphatic)₂, —S(═O)₁₋₂N(C₃₋₁₂-cycloaliphatic)₂,—S(═O)₁₋₂N(aryl)₂, —S(═O)₁₋₂N(heteroaryl)₂,—S(═O)₁₋₂N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—S(═O)₁₋₂N(C₁₋₈-aliphatic-aryl)₂,—S(═O)₁₋₂N(C₁₋₈-aliphatic-heteroaryl)₂, —OS(═O)₁₋₂C₁₋₈-aliphatic,—OS(═O)₁₋₂C₃₋₁₂-cycloaliphatic, —OS(═O)₁₋₂aryl, —OS(═O)₁₋₂heteroaryl,—OS(═O)₁₋₂C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OS(═O)₁₋₂C₁₋₈-aliphatic-aryl, —OS(═O)₁₋₂C₁₋₈-aliphatic-heteroaryl,—OS(═O)₁₋₂OH, —OS(═O)₁₋₂OC₁₋₈-aliphatic,—OS(═O)₁₋₂OC₃₋₁₂-cycloaliphatic, —OS(═O)₁₋₂Oaryl, —OS(═O)₁₋₂Oheteroaryl,—OS(═O)₁₋₂OC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OS(═O)₁₋₂OC₁₋₈-aliphatic-aryl, —OS(═O)₁₋₂OC₁₋₈-aliphatic-heteroaryl,—OS(═O)₁₋₂NH₂, —OS(═O)₁₋₂NHC₁₋₈-aliphatic,—OS(═O)₁₋₂NHC₃₋₁₂-cycloaliphatic, —OS(═O)₁₋₂NHaryl,—OS(═O)₁₋₂NHheteroaryl, —OS(═O)₁₋₂NHC₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—OS(═O)₁₋₂NHC₁₋₈-aliphatic-aryl, —OS(═O)₁₋₂NHC₁₋₈-aliphatic-heteroaryl,—OS(═O)₁₋₂N(C₁₋₈-aliphatic)₂, —OS(═O)₁₋₂N(C₃₋₁₂-cycloaliphatic)₂,—OS(═O)₁₋₂N(aryl)₂, —OS(═O)₁₋₂N(heteroaryl)₂,—OS(═O)₁₋₂N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—OS(═O)₁₋₂N(C₁₋₈-aliphatic-aryl)₂ or—OS(═O)₁₋₂N(C₁₋₈-aliphatic-heteroaryl)₂.

More preferably, R₄ is —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl,-heteroaryl, —O—C₁₋₈-aliphatic, —O—C₃₋₁₂-cycloaliphatic, —O-aryl,—O-heteroaryl, —NH—C₁₋₈-aliphatic, —NH—C₃₋₁₂-cycloaliphatic, —NH-aryl,—NH-heteroaryl, —N(C₁₋₈-aliphatic)₂, —N(C₃₋₁₂-cycloaliphatic)₂,—N(aryl)₂, —N(heteroaryl)₂, —S—C₁₋₈-aliphatic, —S—C₃₋₁₂-cycloaliphatic,—S-aryl or —S-heteroaryl.

Still more preferably, R₄ represents —C₃₋₁₂-cycloaliphatic, -aryl,-heteroaryl, —O—C₁₋₈-aliphatic, —O—C₃₋₁₂-cycloaliphatic, —O-aryl,—O-heteroaryl, —NH—C₁₋₈-aliphatic, —NH—C₃₋₁₂-cycloaliphatic, —NH-aryl,—NH-heteroaryl, —N(C₁₋₈-aliphatic)₂, —N(C₃₋₁₂-cycloaliphatic)₂,—N(aryl)₂, —N(heteroaryl)₂, —S—C₁₋₈-aliphatic, —S—C₃₋₁₂-cycloaliphaticor —S-aryl or —S-heteroaryl.

Particularly preferably, R₄ represents -aryl (preferably -phenyl,optionally substituted), —O-aryl (preferably —O-phenyl, optionallysubstituted) or -heteroaryl (preferably -indolyl or -indanyl, in eachcase optionally substituted). In a particularly preferred embodiment, R₄represents -aryl, -heteroaryl, —C₃₋₁₂-cycloaliphatic, —O-aryl,—O-heteroaryl, —O—C₃₋₁₂-cycloaliphatic, —NH-aryl, —NH-heteroaryl,—NH—C₃₋₁₂-cycloaliphatic, —N(aryl)₂, —N(heteroaryl)₂,—N(C₃₋₁₂-cycloaliphatic)₂, —S-aryl, —S-heteroaryl or—S—C₃₋₁₂-cycloaliphatic; -aryl, -heteroaryl and —C₃₋₁₂-cycloaliphaticbeing particularly preferred.

Preferred examples of R₄ are shown below:

Preferably, R₅ represents —H, —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic,-aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C(═O)H,—C(═O)—C₁₋₈-aliphatic, —C(═O)—C₃₋₁₂-cycloaliphatic, —C(═O)-aryl,—C(═O)-heteroaryl, —C(═O)—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C(═O)—C₁₋₈-aliphatic-aryl, —C(═O)—C₁₋₈-aliphatic-heteroaryl,—C(═O)O—C₁₋₈-aliphatic, —C(═O)O—C₃₋₁₂-cycloaliphatic, —C(═O)O-aryl,—C(═O)O-heteroaryl, —C(═O)O—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C(═O)O—C₁₋₈-aliphatic-aryl, —C(═O)O—C₁₋₈-aliphatic-heteroaryl, —CN,—C(═O)NH₂, —C(═O)—NH—C₁₋₈-aliphatic, —C(═O)NH—C₃₋₁₂-cycloaliphatic,—C(═O)NH-aryl, —C(═O)NH-heteroaryl,—C(═O)—NH—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C(═O)NH—C₁₋₈-aliphatic-aryl, —C(═O)NH—C₁₋₈-aliphatic-heteroaryl,—C(═O)N(C₁₋₈-aliphatic)₂, —C(═O)N(C₃₋₁₂-cycloaliphatic)₂,—C(═O)N(aryl)₂, —C(═O)N-(heteroaryl)₂,—C(═O)N(C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic)₂,—C(═O)N(C₁₋₈-aliphatic-aryl)₂ or —C(═O)—N(C₁₋₈-aliphatic-heteroaryl)₂.

More preferably, R₅ is chosen from —H, —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic,—C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, -aryl and -heteroaryl.

Preferred examples of R₅≠—H are shown below:

In a preferred embodiment, R₅ represents —H.

Particularly preferred embodiments of the compounds according to theinvention are summarized in the following table:

preferably more preferably still more preferably R₁ —H or —H orC₁₋₈-alkyl —H or —CH₃ —C₁₋₈-aliphatic R₂ —H or —H or C₁₋₈-alkyl —H or—CH₃ —C₁₋₈-aliphatic R₃ —C₁₋₈-aliphatic; aryl, —C₁₋₈-alkyl; -butyl,-phenyl, optionally substi- -phenyl, optionally -methoxyphenyl, ortuted; or heteroaryl, substituted; or -fluorophenyl optionallysubstituted -thienyl, optionally substituted R₄ -aryl, —O-aryl, -phenyl,-phenyl, —O-phenyl, —S-aryl, -heteroaryl, —O-phenyl, —S-phenyl, in each—O—C₁₋₈-aliphatic- —S-phenyl, in case optionally sub- aryl, each caseoption- stituted; indolyl, —O—C₃₋₁₂-cyclo- ally substituted; optionallysubstituted; aliphatic indolyl, optionally isoindolyl, optionallysubstituted, iso- substituted; indolyl, optionally —O—C₃₋₁₂-cycloalkylsubstituted; —O—C₃₋₁₂-cyclo- alkyl R₅ —H —H —H Y₁, Y₁′, —H —H —H Y₂,Y₂′, Y₃, Y₃′, Y₄, Y₄′

For the purpose of the description, hydrocarbon radicals are dividedinto aliphatic hydrocarbon radicals on the one hand and aromatichydrocarbon radicals on the other hand.

Aliphatic hydrocarbon radicals are in their turn divided into non-cyclicaliphatic hydrocarbon radicals on the one hand (=“aliphatic”) and cyclicaliphatic hydrocarbon radicals, i.e. alicylic hydrocarbon radicals, onthe other hand (=“cycloaliphatic”). Cycloaliphatics can be monocyclic ormulticyclic. Alicyclic hydrocarbon radicals (“cycloaliphatic”) includeboth pure aliphatic carbocyclyls and aliphatic heterocyclyls, i.e. —ifnot expressly specified—“cycloaliphatic” includes pure aliphaticcarbocyclyls (e.g. cyclohexyl), pure aliphatic heterocyclyls (e.g.piperidyl or piperazyl) and non-aromatic, multicyclic, optionally mixedsystems (e.g. decalinyl, decahydroquinolinyl).

Aromatic hydrocarbon radicals are in their turn divided into carbocyclicaromatic hydrocarbons on the one hand (=“aryl”) and heterocyclicaromatic hydrocarbon radicals on the other hand (=“heteroaryl”).

The assignment of multicyclic, at least partly aromatic systemspreferably depends on whether at least one aromatic ring of themulticyclic system contains at least one hetero atom (conventionally N,O or S) in the ring. If at least one such hetero atom is present in thisring, the radical is preferably a “heteroaryl” (even if a furthercarbocyclic aromatic or non-aromatic ring with or without a hetero atomis present optionally as an additionally present ring of the multicyclicsystem); if such a hetero atom is present in none of the optionallyseveral aromatic rings of the multicyclic system, the radical ispreferably “aryl” (even if a ring hetero atom is present in anoptionally additionally present non-aromatic ring of the multicyclicsystem).

Within the multicyclic substituents, the following priority ofassignment accordingly preferably applies:heteroaryl>aryl>cycloaliphatic. The following substituent is thereforepreferably interpreted as “aryl”:

For the purpose of the description, monovalent and polyvalent, e.g.divalent hydrocarbon radicals are not differentiated with respect toterminology, i.e. “C₁₋₃-aliphatic” includes, depending on the sense,e.g. both —C₁₋₃-alkyl, —C₁₋₃-alkenyl and —C₁₋₃-alkynyl and e.g.—C₁₋₃-alkylene-, —C₁₋₃-alkenylene- and —C₁₋₃-alkynylene-.

Preferably, “aliphatic” is in each case a branched or unbranched,saturated or a mono- or polyunsaturated, unsubstituted or mono- orpolysubstituted, aliphatic hydrocarbon radical. If aliphatic is mono- orpolysubstituted, the substituents independently of each other are chosenfrom the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀,—C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)—N(R₀)₂, —SH, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀,—N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂,—NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂. “Aliphatic” thusincludes acyclic saturated or unsaturated hydrocarbon radicals, whichcan be branched or straight-chain, i.e. alkanyls, alkenyls and alkynyls.In this context, alkenyls have at least one C═C double bond and alkynylshave at least one C≡C triple bond. Preferred unsubstituted monovalentaliphatics include —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂CH₂—CH₂CH₃ and—CH₂CH₂—CH₂CH₂CH₂CH₃; but also —CH═CH₂, —C≡CH, —CH₂CH═CH₂, —CH═CHCH₃,—CH₂C≡CH, —C≡CCH₃ and —CH═CHCH═CH₂. Preferred unsubstituted divalentaliphatics include —CH₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH₂—,—CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)—CH₂—, —CH₂CH₂CH(CH₃)—,—CH—(CH₂CH₃)CH₂— and —CH₂CH₂—CH₂CH₂—; but also —CH═CH—, C≡C—,—CH₂CH═CH—, —CH═CHCH₂—, —CH₂C≡C— and —C≡CCH₂—. Preferred substitutedmonovalent aliphatics include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,—CH₂OH, —CH₂CH₂OH, —CH₂CHOHCH₃, —CH₂OCH₃ and CH₂CH₂OCH₃. Preferredsubstituted divalent aliphatics include —CF₂—, —CF₂CF₂—, —CH₂CHOH—,—CHOHCH₂— and —CH₂CHOHCH₂—. Methyl, ethyl, n-propyl and n-butyl areparticularly preferred

Preferably, cycloaliphatic is in each case a saturated or a mono- orpolyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic(i.e. not aromatic), mono- or multicyclic hydrocarbon radical, Thenumber of ring carbon atoms is preferably in the stated range (i.e. a“C₃₋₈-”cycloaliphatic preferably has 3, 4, 5, 6, 7 or 8 ring carbonatoms). For the purpose of the description, “C₃₋₈-cycloaliphatic” ispreferably a cyclic hydrocarbon having 3, 4, 5, 6, 7 or 8 ring carbonatoms, saturated or unsaturated, but not aromatic, one or two carbonatoms independently of each other optionally being replaced by a heteroatom S, N or O. If cycloalkyl is mono- or polysubstituted, thesubstituents independently of each other are chosen from the groupconsisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀,—C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀,—OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀,—SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,—N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀,—NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂. C₃₋₈-Cycloaliphatic isadvantageously chosen from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but alsotetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl,piperazinyl, pyrazolinonyl and pyrrolidinyl. If cycloaliphatic issubstituted by R₀ and R₀ represents aryl or heteroaryl, this aryl orheteroaryl substituent can be bonded via a bond to cycloaliphatic, butit can also be bonded via two vicinal ring atoms of the cycloaliphatic,i.e. fused.

Preferably, in connection with “aliphatic” or “cycloaliphatic”, “mono-or polysubstituted” is understood as meaning substitution once orseveral times, e.g. once, twice, three times or four times, of one ormore hydrogen atoms by —F, —Cl, —Br, —I, —OH, —OC₁₋₆-alkyl,—OC(═O)C₁₋₆-alkyl, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compounds wherein “aliphatic substituted”or “cycloaliphatic substituted” means aliphatic or cycloaliphaticsubstituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH,—CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂ are preferred. Particularlypreferred substituents are —F, —Cl, —OH, —SH, —NH₂ and —C(═O)OH.

Polysubstituted radicals are to be understood as meaning those radicalswhich are polysubstituted, e.g. di- or trisubstituted, either ondifferent or on the same atoms, for example trisubstituted on the same Catom, as in the case of —CF₃ or —CH₂CF₃, or at different places, as inthe case of —CH(OH)—CH═CH—CHCl₂. Polysubstitution can be with the sameor with various substituents. A substituent can optionally also besubstituted in its turn; thus -Oaliphatic, inter alia, also includes—O—CH₂CH₂O—CH₂CH₂—OH. It is preferable for aliphatic or cycloaliphaticto be substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂,—SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂. It is very particularlypreferable for aliphatic or cycloaliphatic to be substituted by —OH,—OCH₃ or —OC₂H₅.

Preferably, aryl in each case independently represents a carbocyclicring system having at least one aromatic ring, but without hetero atomsin this ring, wherein the aryl radicals can optionally be fused withfurther saturated, (partially) unsaturated or aromatic ring systems,which in their turn can have one or more hetero ring atoms, in each caseindependently of each other chosen from N, O and S, and wherein eacharyl radical can be unsubstituted or mono- or polysubstituted, whereinthe substituents on aryl can be identical or different and can be in anydesired and possible position of the aryl. Preferred aryls are phenyl,naphthyl, anthracenyl, phenanthrenyl, fluoranthenyl, fluorenyl, indanyland tetralinyl. Phenyl and naphthyl are particularly preferred. If arylis mono- or polysubstituted, the substituents on aryl can be identicalor different and can be in any desired and possible position of thearyl, and are independently of each other chosen from the groupconsisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀,—C(═O)OH, —C(═O)OR₀, —C(═O)—NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH,—O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)—NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,—NHC(═O)NH₂, —NHC(═O)NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂.Preferred substituted aryls are 2-fluoro-phenyl, 3-fluoro-phenyl,4-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl,3,4-difluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl,2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethyl-phenyl,2,4-dimethyl-phenyl and 3,4-dimethyl-phenyl.

Preferably, heteroaryl represents a 5-, 6- or 7-membered cyclic aromaticradical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the heteroatoms are identical or different and are nitrogen, oxygen or sulfur andthe heterocyclyl can be unsubstituted or mono- or polysubstituted;wherein in the case of substitution on the heterocyclyl the substituentscan be identical or different and can be in any desired and possibleposition of the heteroaryl; and wherein the heterocyclyl can also bepart of a bi- or polycyclic system. Preferably, “heteroaryl” is chosenfrom the group consisting of pyrrolyl, indolyl, furyl (furanyl),benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl,benzooxadiazolyl, benzothiazolyl, benzooxazolyl, benzotriazolyl,benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl,isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl oroxadiazolyl, where bonding can be via any desired and possible ringmember of the heteroaryl radical. If heteroaryl is mono- orpolysubstituted, the substituents on heteroaryl can be identical ordifferent and in any desired and possible position of the heteroaryl,and are independently of each other chosen from the group consisting of—F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH,—C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀,—OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀,—S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O—,—NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂,—Si(R₀)₃, —PO(OR₀)₂.

With respect to “aryl” or “heteroaryl”, “mono- or polysubstituted” isunderstood as meaning substitution once or several times, e.g. twice,three times, four times or five times, of one or more hydrogen atoms ofthe ring system.

The substituents on aryl and heteroaryl are particularly preferably ineach case independently of each other chosen from —F, —Cl, —Br, —I, —CN,—CHO, —CO₂H, —NH₂, —NO₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —SH,—SR₀, —OH, —OR₀, —C(═O)R₀, —CO₂R₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂,—S(═O)₁₋₂R₀, —S(═O)₁₋₂NH₂, —SO₃H, ═O or —R₀. Preferred substituents are—F, —Cl, —Br, —I, —OH, —OC₁₋₆-alkyl, —O—C(═O)—C₁₋₆-alkyl, —SH, —NH₂,—NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compoundswherein “aryl substituted” or “heteroaryl substituted” means aryl orheteroaryl substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂,—NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂ are preferred.Particularly preferred substituents are —F, —Cl, —OH, —SH, —NH₂ and—C(═O)OH.

The compounds according to the invention can be in the form of anindividual stereoisomer or mixture thereof, the free compounds and/ortheir physiologically acceptable salts and/or solvates.

The compounds according to the invention can be chiral or achiral,depending on the substitution pattern.

Depending on the substitution with respect to the cyclohexane ring, thecompounds according to the invention can be isomers in which thesubstitution pattern in the 1,4-position (1-position: >C(NR₁R)R₃;4-position: >COHR₅CH₂R₄) can also be called syn/anti. “Syn/anti isomers”are a sub-group of stereoisomers (configuration isomers).

In a preferred embodiment, the diastereomer excess of the syn isomer isat least 50% de, more preferably at least 75% de, still more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de. In another preferred embodiment, the diastereomer excessof the anti isomer is at least 50% de, more preferably at least 75% de,still more preferably at least 90% de, most preferably at least 95% deand in particular at least 99% de.

Suitable methods for separation of the isomers (diastereomers) are knownto the person skilled in the art. Examples which may be mentioned arecolumn chromatography, preparative HPLC and crystallization processes.

If the compounds according to the invention are chiral, they arepreferably in the form of the racemate or in an enriched form of oneenantiomer. In a preferred embodiment, the enantiomer excess (ee) of theS enantiomer is at least 50% ee, more preferably at least 75% ee, stillmore preferably at least 90% ee, most preferably at least 95% ee and inparticular at least 99% ee. In another preferred embodiment, theenantiomer excess (ee) of the R enantiomer is at least 50% ee, morepreferably at least 75% ee, still more preferably at least 90% ee, mostpreferably at least 95% ee and in particular at least 99% de.

Suitable methods for separation of the enantiomers are known to theperson skilled in the art. Examples which may be mentioned arepreparative HPLC on chiral stationary phases and conversion intodiastereomeric intermediates. The conversion into diastereomericintermediates can be carried out, for example, as salt formation withthe aid of chiral, enantiomerically pure acids. After the separation ofthe diastereomers formed in this way, the salt can then be convertedback into the free base or another salt.

If not expressly specified, any reference to the compounds according tothe invention includes all the isomers (e.g. stereoisomers,diastereomers, enantiomers) in any desired mixing ratio.

If not expressly stated, any reference to the compounds according to theinvention includes the free compounds (i.e. the forms which are not inthe form of a salt) and all physiologically acceptable salts.

For the purpose of the description, physiologically acceptable salts ofthe compounds according to the invention are in the form of salts withanions or acids of the particular compound with inorganic or organicacids which are physiologically acceptable—in particular when used inhumans and/or mammals.

Examples of physiologically acceptable salts of particular acids aresalts of: hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid, saccharic acid, monomethylsebacicacid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-liponic acid,acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.The hydrochloride, the citrate and the hemicitrate are particularlypreferred.

Physiologically acceptable salts with cations or bases are salts of theparticular compound—as the anion with at least one, preferably inorganiccation—which are physiologically acceptable—in particular when used inhumans and/or mammals. The salts of alkali metals and alkaline earthmetals but also ammonium salts are particularly preferred, but inparticular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium orcalcium salts.

Preferred embodiments of the compounds according to the invention are ineach case explained in the following. If not expressly specified, allthe particular definitions explained above for the substituents and theparticular preferred embodiments thereof apply accordingly and aretherefore not repeated.

Preferred embodiments of the compounds of the general formula (1)according to the invention have the general formula (2), (3), (4), (5),(6), (7), (8) or (9).

wherein, if present,

-   R_(A) represents —H, —F, —Cl, —CN, —NO₂ or —OCH₃ and-   (Hetero-)aryl represents heteroaryl or aryl, in each case    unsubstituted or mono- or polysubstituted.

The compounds according to the invention are defined by substituents,for example by R₁, R₂ and R₃ (substituents of the 1st generation), whichin their turn are optionally substituted (substituents of the 2ndgeneration). Depending on the definition, these substituents of thesubstituents can in their turn be substituted again (substituents of the3rd generation). For example, if Y₁=R₀, wherein R₀=—C₁₋₈-aliphatic(substituent of the 1st generation), —C₁₋₈-aliphatic can in its turn besubstituted, e.g. by —OR₀, wherein R₀=-aryl (substituent of the 2ndgeneration). The functional group —C₁₋₈-aliphatic-Oaryl results fromthis. -Aryl can then in its turn be substituted again, e.g. by —Cl(substituents of the 3rd generation). The functional group—C₁₋₈-aliphatic-Oaryl-Cl overall then results from this.

In a preferred embodiment, however, the substituents of the 3rdgeneration cannot be substituted again, i.e. there are then nosubstituents of the 4th generation.

In another preferred embodiment, however, the substituents of the 2ndgeneration cannot be substituted again, i.e. there are then already nosubstituents of the 3rd generation. In other words, in this embodimentthe functional groups for R₀ to R₅ can in each case be optionallysubstituted, but the particular substituents cannot then in their turnbe substituted again.

In another preferred embodiment, the substituents of the 1st generationalready cannot be substituted again, i.e. there are then neithersubstituents of the 2nd nor substituents of the 3rd generation. In otherwords, in this embodiment the functional groups for R₀ to R₅ in eachcase cannot be substituted.

Very particularly preferred compounds are those from the group:

-   -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenylethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenoxyethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(1H-indol-1-yl)ethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(isoindolin-2-yl)ethanol,    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(4-fluorophenyl)ethanol;    -   1-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-phenylethanol;    -   1-(4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-2-phenylethanol;    -   1-(4-(dimethylamino)-4-(thiophen-2-yl)cyclohexyl)-2-phenylethanol;    -   1-(4-butyl-4-(dimethylamino)cyclohexyl)-2-phenylethanol;    -   1-cyclopentyl-2-(4-(dimethylamino)-4-phenylcyclohexyl)-3-phenylpropan-2-ol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-2-(pyridin-4-yl)ethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylthio)ethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylsulfonyl)ethanol;    -   2-(cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;    -   2-(benzyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenethoxyethanol;    -   2-((1H-indol-3-yl)methoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;    -   2-(2-(1H-indol-3-yl)ethoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;    -   1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-((2-(triethylsilyl)-1H-indol-3-yl)methoxy)ethanol;    -   1-(2-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-hydroxyethyl)piperidin-2-one;    -   2-(4,4a-dihydro-1H-pyrido[3,4-b]indol-2(3H,9H,9aH)-yl)-1-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)ethanol;    -   1-cinnamoyl-3-(2-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one;    -   2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenylpropan-2-ol;    -   2-(4-(dimethylamino)-4-phenylcyclohexyl)-1,3-diphenylpropan-2-ol;    -   2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-2-yl)propan-2-ol;    -   2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-3-yl)propan-2-ol;        and    -   2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-4-yl)propan-2-ol;        and physiologically acceptable salts and/or solvates thereof.

Further preferred compounds are

-   -   2-(9-(benzenesulfonyl)-2,3,4,9-tetrahydro-1H-beta-carbolin-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol;    -   2-(2,3-dihydro-1H-isoindol-2-yl)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;    -   2-cyclohexyloxy-1-(4-dimethylamino-4-thiophen-2-ylcyclohexyl)ethanol;    -   2-(4-dimethylamino-4-phenylcyclohexyl)-1-phenoxy-propan-2-ol;        and    -   3-((3S)-3-(4-dimethylamino-4-phenylcyclohexyl)-3-hydroxy-prop-1-ynyl)-1H-indole-1-carboxylic        acid tert-butyl ester;        and physiologically acceptable salts thereof.

The compounds according to the invention act, for example, on the ORL1receptor relevant in connection with various diseases, so that they aresuitable as a pharmaceutical active compound in a medicament.

The invention therefore also provides medicaments which contain at leastone compound according to the invention and optionally suitableadditives and/or auxiliary substances and/or optionally further activecompounds.

The compounds according to the invention have a comparable affinity forthe μ opioid or for the ORL1 receptor to the compounds which aredisclosed as example compounds in WO 2004043967. Compared with thesecompounds, however, they have a higher solubility and are thereforesuitable in particular for the development of medicaments.

The medicaments according to the invention optionally contain, inaddition to at least one compound according to the invention, suitableadditives and/or auxiliary substances, that is to say also carriermaterials, fillers, solvents, diluents, dyestuffs and/or binders, andcan be administered as liquid medicament forms in the form of injectionsolutions, drops or juices or as semi-solid medicament forms in the formof granules, tablets, pellets, patches, capsules, plasters/spray-onplasters or aerosols. The choice of auxiliary substances etc. and theamounts thereof to be employed depend on whether the medicament is to beadministered orally, perorally, parenterally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,buccally, rectally or locally, for example on the skin, the mucousmembranes or into the eyes. Formulations in the form of tablets, coatedtablets, capsules, granules, drops, juices and syrups are suitable fororal administration, and solutions, suspensions, easily reconstitutabledry formulations and sprays are suitable for parenteral, topical andinhalatory administration. Compounds according to the invention in adepot, in dissolved form or in a plaster, optionally with the additionof agents which promote penetration through the skin, are suitableformulations for percutaneous administration. Formulation forms whichcan be used orally or percutaneously can release the compounds accordingto the invention in a delayed manner. The compounds according to theinvention can also be used in parenteral long-term depot forms, such ase.g. implants or implanted pumps. In principle, other further activecompounds known to the person skilled in the art can be added to themedicaments according to the invention.

The amount of active compound to be administered to patients varies as afunction of the weight of the patient, of the mode of administration,the indication and the severity of the disease. 0.00005 to 50 mg/kg,preferably 0.001 to 0.5 mg/kg of at least one compound according to theinvention are conventionally administered.

For all the above forms of the medicaments according to the invention,it is particularly preferable if the medicament also contains, inaddition to at least one compound according to the invention, a furtheractive compound, in particular an opioid, preferably a potent opioid, inparticular morphine, or an anaesthetic, preferably hexobarbital orhalothane.

In a preferred form of the medicament, a compound according to theinvention contained therein is in the form of a pure diastereomer and/orenantiomer.

The ORL1 receptor has been identified in particular in the pain event.Compounds according to the invention can accordingly be used for thepreparation of a medicament for treatment of pain, in particular acute,neuropathic or chronic pain.

The invention therefore also provides the use of a compound according tothe invention for the preparation of a medicament for treatment of pain,in particular acute, visceral, neuropathic or chronic pain.

The invention also provides the use of a compound according to theinvention for the preparation of a medicament for treatment of anxietystates, of stress and syndromes associated with stress, depression,epilepsy, Alzheimer's disease, senile dementia, general cognitivedysfunctions, learning and memory disorders (as a nootropic), withdrawalsymptoms, alcohol and/or drug and/or medicament abuse and/or dependency,sexual dysfunctions, cardiovascular diseases, hypotension, hypertension,tinnitus, pruritus, migraine, impaired hearing, lack of intestinalmotility, impaired food intake, anorexia, obesity, locomotor disorders,diarrhoea, cachexia, urinary incontinence or as a muscle relaxant,anticonvulsive or anaesthetic or for co-administration in treatment withan opioid analgesic or with an anaesthetic, for diuresis orantinatriuresis, anxiolysis, for modulation of motor activity, formodulation of neurotransmitter secretion and treatment ofneurodegenerative diseases associated therewith, for treatment ofwithdrawal symptoms and/or for reduction of the addiction potential ofopioids.

In this context, in one of the above uses it may be preferable for acompound which is used to be in the form of a pure diastereomer and/orenantiomer, a racemate or a non-equimolar or equimolar mixture of thediastereomers and/or enantiomers.

The invention also provides a method for the treatment, in particular inone of the abovementioned indications, of a non-human mammal or a humanrequiring treatment of pain, in particular chronic pain, byadministration of a therapeutically active dose of a compound accordingto the invention, or of a medicament according to the invention.

The present invention also provides a process for the preparation of thecompounds according to the invention as described in the followingdescription and examples. In this context, a process for the preparationof a compound according to the invention wherein compounds of thegeneral formula I can be obtained by addition of suitable nucleophileson to suitable carbonyl compounds is suitable in particular. In the casewhere R⁵ differs from —H, either R⁵ or R⁴—CH₂ can be introduced in avarying sequence (equation 1):

In this context, the ketones II or III can be introduced in anintermediate synthesis by addition of suitable carbon nucleophiles on toaldehydes VI. The alcohol V obtained can then be converted into theketones II or III by means of oxidation methods familiar to the personskilled in the art. Alternatively to this, carbonyl compounds of theWeinreb amide type (IV) can be converted into ketones by substitutionwith carbon nucleophiles (equation 2):

The preparation of Weinreb amides is known to the person skilled in theart.

In the case where R⁵ is identical to R⁴—CH₂—, compounds of the generalformula I can also be obtained by addition of at least 2 equivalents ofa suitable carbon nucleophile on to corresponding carboxylic acidsesters or other suitable carbonyl compounds.

In the case where R⁵ is —H, intermediate stages V and VI are eliminated.

An alternative process for the preparation of compounds of the generalformula I comprises ring-opening substitution by means of suitablenucleophiles containing R⁴ on terminal epoxides VII (equation 3). Inthis context, acetal-protected precursors VIII, preferably ketals, canadvantageously be used as starting substances. The ketal VIII resultingfrom ring-opening substitution is deprotected to give IX. In a furtherstep, a suitable protective group is introduced on to the alcoholfunction, e.g. another acetal, resulting in compounds of the generalformula X. The keto functions obtained beforehand are converted intoaminonitriles XI by processes known to the person skilled in the art,which are then converted into amines of the type XII with carbonnucleophiles by familiar methods. The compounds of the general formula Iare then obtained by removal of the acetal protective group on thealcohol.

This process is particularly advantageous in the case where R⁴ is bondedvia a hetero atom, i.e. R⁴ starts with a hetero atom chosen from N, Sand O.

Terminal epoxides of the type VII can be prepared by processes known tothe person skilled in the art. e.g. by addition of methylides on tosuitable carbonyl compounds III or e.g. by epoxidation of correspondingolefins XIV (equation 4):

With respect to further details of the synthesis of the compoundsaccording to the invention, reference may be made in full scope toWO2002/090317, WO2002/90330, WO2003/008370, WO2003/008731,WO2003/080557, WO2004/043899, WO2004/043900, WO2004/043902,WO2004/043909, WO2004/043949, WO2004/043967, WO2005/063769,WO2005/066183, WO2005/110970, WO2005/110971, WO2005/110973,WO2005/110974, WO2005/110975, WO2005/110976, WO2005/110977,WO2006/018184, WO2006/108565, WO2007/079927, WO2007/079928,WO2007/079930, WO2007/079931, WO2007/124903, WO2008/009415 andWO2008/009416.

EXAMPLES

The following examples serve to illustrate the invention in more detail,but are not to be interpreted as limiting.

The yields of the compounds prepared are not optimized. All thetemperatures are uncorrected. The term “ether” means diethyl ether, “EA”ethyl acetate and “MC” methylene chloride. The term “equivalent” meansequivalent substance amount, “m.p.” melting point or melting range,“decomp.” decomposition, “RT” room temperature, “abs.” absolute(anhydrous), “rac.” racemic, “conc.” concentrated, “min” minutes, “h”hours, “d” days, “vol. %” percent by volume, “wt. %” percent by weight,and “M” is a concentration stated in mol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was employed asthe stationary phase for the column chromatography. The thin layerchromatography investigations were carried out with HPTLC precoatedplates, silica gel 60 F 254 from E. Merck, Darmstadt. The mixing ratiosof mobile phases for chromatography investigations are always stated involume/volume.

-   ¹H-NMR: Varian Mercury 400BB, 400 MHz or Varian Mercury 300 BB, 300    MHz;-   ¹³C-NMR: Varian Mercury 400BB, 100 MHz or Varian Mercury 300 BB, 75    MHz;-   internal standard: TMS, chemical shifts in ppm; br: broad signal-   ¹⁹F-NMR: Varian Mercury 400BB, 376.8 MHz-   internal standard: CFCl₃

LC-MS: Agilent LC-MS 1200 Rapid Resolution with MSD6140

Gradient: Time 0 min: 95% water (+1% formic acid)/5% methanol (+1%formic acid)→time 5.4 min: 0% water/100% methanol+1% formic acid)

Column temperature: 50° C.; injection volume: 5 μl; flow rate 0.8ml/min; fragmenter voltage: 100 V [pos/neg]; detection: MM-ES+APCI+DAD(254 nm); column: SB-C18, 2.1 mm×30 mm, 3.5 micron.

Method Duration Flow rate No. [min] [ml/min] 1 7 0.8 7 7.5 0.8 8 7 0.8

Continuation of method table LC/MS

Column Wave- Frag- Method temp. length UV Mass Pos/ menting no. Gradient[° C.] [nm] scan range neg [V] 1 5-100 30 254 * 100-800 */* 50 7 5-10050 254 * 100-600 */* 100 8 5-100 80 254 *  80-800 */* 100

Example 11-(4-Dimethylamino-4-(3-fluoro-phenyl)cyclohexyl)-2-phenyl-ethanol

Stage 1 4-Dimethylamino-4-(3-fluorophenyl)cyclohexanecarbaldehyde

A 60% dispersion of sodium hydride in mineral oil (254 mg, 6.36 mmol)was added to a suspension of methoxymethyltriphenylphosphonium chloride(2.18 g, 6.36 mmol) in anhydrous tetrahydrofuran (5 ml) and anhydrousN,N-dimethylformamide (5 ml) under argon. The mixture was stirred atroom temperature for 2 h. A solution of4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (1.0 g, 4.24 mmol) inanhydrous tetrahydrofuran (5 ml) and anhydrous N,N-dimethylformamide (5ml) was then added dropwise in the course of 30 min and the mixture wasstirred at room temperature overnight. 2 M hydrochloric acid (25 ml) wasthen added dropwise, while cooling with ice, and the mixture was stirredat room temperature for 5 h. Thereafter, the mixture was extracted withethyl acetate (5×20 ml) and diethyl ether (3×20 ml). The aqueous phasewas adjusted to pH 11 with 4 M sodium hydroxide solution and extractedwith ethyl acetate (4×20 ml). The combined organic extracts from thealkaline solution were dried with sodium sulfate and concentrated i.vac.

Yield: 1.49 g (>100%), brown oil

¹H-NMR (DMSO-d₆): The product is a diastereoisomer mixture. All thecharacteristic signals could be identified.

Stage 21-(4-Dimethylamino-4-(3-fluoro-phenyl)cyclohexyl)-2-phenyl-ethanol

A 2 M solution of benzylmagnesium chloride in tetrahydrofuran (6.00 ml,12 mmol) was added dropwise to a solution of4-dimethylamino-4-(3-fluorophenyl)cyclohexanecarbaldehyde (1.49 g, 5.97mmol) in anhydrous tetrahydrofuran (30 ml), while cooling with ice. Themixture was stirred at room temperature for 2 d and saturated ammoniumchloride solution (30 ml) was then added, while cooling with ice. Thetetrahydrofuran was removed i. vac. and the residue was brought to pH 8with 4 M sodium hydroxide solution. The aqueous suspension was extractedwith diethyl ether (3×30 ml). The combined organic phases were driedwith sodium sulfate and concentrated i. vac. The crude product (2.18 g)was purified by flash chromatography with methylene chloride/methanol[95:5+1% NH₃ (32% in H₂O)]. The impure polar diastereoisomer (500 mg)was purified again by flash chromatography with methylenechloride/methanol [95:5+1% NH₃ (32% in H₂O)].

-   Yield: 125 mg (6%), white solid-   Melting point: 170° C.

¹H-NMR (DMSO-d₆): 0.56-1.10 (m, 2H); 1.20-1.60 (m, 4H); 1.74 (br d, 1H,J=13.0 Hz); 1.91 (s, 6H); 2.46 (m, 1H, overlapped by the DMSO signal);2.56-2.70 (m, 3H); 3.27 (m, 1H); 4.23 (d, 1H, J=6.0 Hz); 7.02-7.25 (m,8H); 7.41 (dd, 1H, J=7.9 and 14.5 Hz).

¹³C-NMR (DMSO-d₆): 23.2; 25.8; 32.4; 32.7; 37.9; 40.7; 42.8; 61.0; 74.5;112.8 (d, J=21 Hz); 114.6 (d, J=21 Hz); 123.9; 125.3; 127.8; 129.2;140.2; 162.2 (d, J=242 Hz).

Example 2 1-(4-Butyl-4-dimethylaminocyclohexyl)-2-phenylethanol

By replacing 4-dimethylamino-4-(3-fluorophenyl)cyclohexanone by4-butyl-4-dimethylaminocyclohexanone in Example 1, stage 1 andsubsequent analogous reaction in stage 2, Example 2 was obtained:

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.1 Hz); 1.14-1.49 (9H, m); 1.56-1.82(6H, m); 2.28 (6H, s); 2.63 (1H, dd, J=8.9, 13.6 Hz); 2.88 (1H, dd,J=4.7, 13.6 Hz); 3.66 (1H, m); 7.16-7.22 (3H, m); 7.27-7.29 (2H, m). TheOH proton could not be identified.

¹³C-NMR (CDCl₃): 14.0; 21.8; 23.5; 23.7 (2C); 26.7 (2C); 31.1; 31.7;31.8; 37.0 (2C); 41.0; 42.3; 76.4; 126.0; 128.3 (2C); 129.3 (2C); 139.3.

LC-MS (method 8): [M+H]⁺: m/z=304.3, R_(t)=2.4 min.

Example 3 and Example 4(1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylethanol hydrochloride,Less Polar Diastereomer)(1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylethanol, More PolarDiastereomer)

By replacing 4-dimethylamino-4-(3-fluorophenyl)cyclohexanecarbaldehydeby 4-dimethylamino-4-phenylcyclohexanecarbaldehyde in Example 1, stage2, Examples 3 and 4 were obtained analogously:

-   1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (Nonpolar    Diastereoisomer)-   Yield: 170 mg (16%), yellowish oil.-   ¹H-NMR (CDCl₃): 1.35-1.90 (m, 6H); 2.05 (s, 6H); 2.58-2.72 (m, 3H);    2.94-3.06 (m, 1H); 3.42-3.50 (m, 1H); 3.72 (br s, 1H); 4.20-4.23 (m,    1H); 7.02-7.95 (m, 10H).-   1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (Polar    Diastereoisomer)

Yield: 142 mg (14%), white solid

Melting point: 161-166° C.

¹H-NMR (CDCl₃): 0.99-1.16 (m, 2H); 1.46-1.78 (m, 5H); 1.89-1.98 (m, 1H);2.07 (s, 6H); 2.49 (dd, 1H, J=9.5 and 13.5 Hz); 2.76 (br d, 1H, J=12.5Hz); 2.80 (dd, 1H, J=13.7, 3.2 Hz); 3.40 (ddd, 1H, J=9.6, 6.4, 3.3 Hz);7.11-7.43 (m, 10H).

Stage 2 (1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylethanolhydrochloride, Less Polar Diastereomer)

A 7.5 M solution of hydrogen chloride in diethyl ether (25 ml) was addedto 1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (nonpolarDiastereoisomer, 140 mg, 0.41 mmol). The supernatant solution wasdecanted and the precipitate was dried over potassium hydroxide i. vac.in a desiccator.

Yield: 80 mg (51%), white solid

Melting point: 235° C.

¹H-NMR (DMSO-d₆): 1.29-1.44 (m, 3H); 1.76-1.90 (m, 1H); 1.92-2.04 (m,1H); 2.24-2.38 (m, 2H); 2.43 (t, 6H, J=5.3 Hz); 2.45-2.58 (m, 3H, partlyoverlapped by the DMSO signal); 2.90 (dd, 1H, J=3.1 and 13.7 Hz);3.80-3.88 (m, 1H); 4.44 (s, 1H); 7.13-7.19 (m, 1H); 7.22-7.29 (m, 4H);7.47-7.55 (m, 3H); 7.66-7.71 (m, 2H); 10.48 (s, 1H).

Example 51-(4-Dimethylamino-4-phenylcyclohexyl)-2-(4-fluorophenyl)ethanol

By replacing benzylmagnesium chloride by 4-fluorobenzylmagnesiumchloride in Example 3 and 4, stage 1, Example 5 was obtainedanalogously:

Melting point: 75° C.

¹H-NMR (CDCl₃): 1.32-1.56 (m, 3H); 1.58-1.84 (m, 6H); 2.05 (s, 6H); 2.66(m, 2H); 2.95 (d, 1H, J=13.8 Hz); 3.68 (m, 1H); 6.96-7.05 (m, 2H);7.18-7.40 (m, 7H).

¹³C-NMR (DMSO-d₆): 23.1; 24.1; 32.8; 32.9; 37.8; 40.3; 42.5; 58.9; 76.4;115.2 (d, J=21 Hz); 126.4; 126.6; 127.2; 130.7 (d, J=8 Hz); 134.9;139.6; 161.6 (d, J=244 Hz).

LC-MS (method 8): [M+H]⁺: m/z=342.3, R_(t)=2.4 min.

Example 6 and Example 71-(4-Dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-phenylethanol (PolarDiastereomer) and1-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-phenylethanol (NonpolarDiastereomer)

Stage 1 1-(1,4-Dioxaspiro[4.5]dec-8-Yl)-2-phenylethanol

A 2 M solution of benzylmagnesium chloride (26 ml, 52 mmol) was addeddropwise to a solution of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde (4.42g, 25.9 mmol) in anhydrous tetrahydrofuran (30 ml), while cooling withice. The mixture was stirred at room temperature overnight. Saturatedammonium chloride solution (10 ml) and water (10 ml) were then added tothe reaction mixture, while cooling with ice. The solvent wasconcentrated i. vac. The residue was extracted with diethyl ether (3×10ml). The combined organic phases were dried with sodium sulfate andconcentrated i. vac.

Yield: 2.23 g (32%), white solid

Melting point: 86° C.

¹H-NMR (DMSO-d₆): 1.15-1.85 (m, 9H); 2.54 (dd, 1H, J=13.6, 8.4 Hz); 2.72(dd, 1H, J=13.6, 4.2 Hz); 3.45 (m, 1H); 3.83 (s, 4H); 4.38 (d, 1H; J=6.0Hz); 7.10-7.30 (m, 5H).

In analogous batches with 3 to 48.11 mmol employing from 2 to 4 molarequivalents of benzylmagnesium chloride, yields of from 26 to 47% wereachieved.

Stage 2 4-(1-Hydroxy-2-phenylethyl)cyclohexanone

2 M hydrochloric acid (30 ml) was added to a solution of1-(1,4-dioxaspiro[4.5]dec-8-yl)-2-phenylethanol (2.98 g, 11.3 mmol) intetrahydrofuran (30 ml). The solution was stirred at 50° C. overnight.The mixture was rendered alkaline with 4 M sodium hydroxide solution,the phases were separated and the aqueous phase was extracted withmethylene chloride (3×20 ml). The combined organic phases were driedwith sodium sulfate and concentrated i. vac.

Yield: 2.52 g (100%), colourless oil

¹H-NMR (DMSO-d₆): 1.40-1.80 (m, 3H); 1.90 (m, 1H); 2.08 (m, 1H);2.14-2.42 (m, 4H); 2.61 (dd, 1H, J=8.2 and 13.6 Hz); 2.76 (dd, 1H, J=4.6and 13.6 Hz); 3.59 (m, 1H); 4.57 (d, 1H, J=5.9 Hz); 7.13-7.32 (m, 5H).

Stage 3 4-[1-(1-Ethoxy-ethoxy)-2-phenylethyl]cyclohexanone

Ethyl vinyl ether (998 mg, 1.32 ml, 13.8 mmol) and pyridinium tosylate(44 mg, 0.17 mmol) were added to a solution of4-(1-hydroxy-2-phenylethyl)cyclohexanone (2.52 g, 11.5 mmol) inanhydrous methylene chloride (50 ml) and the mixture was stirred at roomtemperature overnight. Methylene chloride (20 ml) was added to themixture and the mixture was washed with water, 5% sodium bicarbonatesolution and sodium chloride solution (50 ml of each). The combinedorganic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 2.93 g, orange-coloured oil.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals.

The product is a mixture of two diastereoisomers.

Stage 41-Dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile

40% aqueous dimethylamine solution (6.05 ml, 47.9 mmol) was added to amixture of 4 M hydrochloric acid (2.61 ml) and methanol (1.56 ml), whilecooling with ice. A solution of4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanone (2.91 g, 10.0 mmol)in methanol (6 ml) and tetrahydrofuran (3 ml) was added to this mixture.Thereafter, potassium cyanide (1.56 g, 24.1 mmol) was added to themixture, the mixture was stirred at room temperature overnight, water(150 ml) was then added and the mixture was extracted with diethyl ether(4×50 ml). The combined organic phases were dried with sodium sulfateand concentrated i. vac. The residue was taken up in methylene chloride(50 ml) and the mixture was washed with water (30 ml). The organic phasewas dried again with sodium sulfate and concentrated i. vac.

Yield: 3.18 g, orange-coloured oil.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals. Theproduct is a mixture of diastereoisomers.

Stage 5{4-[1-(1-Ethoxy-ethoxy)-2-phenylethyl]-1-thiophen-2-yl-cyclohexyl}dimethylamine

A 1 M solution of 2-thienylmagnesium bromide in tetrahydrofuran (9.25ml, 9.25 mmol) was added dropwise to a solution of1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile(1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with iceand under an argon atmosphere. The mixture was stirred at roomtemperature for 48 h and water and saturated ammonium chloride solution(10 ml of each) were then added. The phases were separated and theaqueous phase was extracted with diethyl ether (3×10 ml). The combinedorganic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 1.12 g, yellowish oil.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals. Theproduct is a mixture of diastereoisomers.

Stage 6 1-(4-Dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-phenylethanol

2 M hydrochloric acid (20 ml) was added to a solution of{4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-thiophen-2-yl-cyclohexyl}dimethylamine(1.10 g, 2.73 mmol) in tetrahydrofuran (20 ml) and the reaction mixturewas stirred at room temperature overnight. It was then rendered alkalinewith 4 M sodium hydroxide solution and extracted with methylene chloride(4×10 ml). The combined organic phases were dried with sodium sulfateand concentrated i. vac. The crude product (956 mg) was purified byflash chromatography with cyclohexane/ethyl acetate (3:2) and thenmethanol. The two product fractions obtained in this way were each takenup in diethyl ether, and 2 M hydrochloric acid (20 ml) was added. Thephases were separated. The acid aqueous phases were extracted withdiethyl ether (3×10 ml) and thereafter rendered alkaline with 4 M sodiumhydroxide solution. The aqueous phases were extracted with methylenechloride (4×10 ml). The combined organic phases were dried with sodiumsulfate and concentrated i. vac.

Polar Diastereoisomer

Yield: 466 mg (46%, based on the stage 2 employed), beige-coloured solid

Melting point: 85° C.

¹H-NMR (DMSO-d₆): 1.22-1.75 (m, 7H); 2.01 (s, 6H); 2.40-2.46 (m, 2H);2.55 (dd, 1H, J=13.6 and 8.6 Hz); 2.75 (dd, 1H, J=13.6 and 4.0 Hz); 3.45(m, 1H); 4.35 (d, 1H, J=6.1 Hz); 6.90 (d, 1H, J=3.5 Hz); 7.03 (dd, 1H,J=3.5 and 5.1 Hz); 7.14-7.30 (m, 5H); 7.37 (d, 1H, J=5.1 Hz).

¹³C-NMR (DMSO-d₆): 22.1; 23.9; 35.1; 35.3; 37.5; 40.6; 42.8; 58.1; 75.1;122.8; 123.5; 125.3; 126.0; 127.7; 129.3; 140.4; 145.2.

LC-MS (method 7): [M+H]⁺: m/z=330.3, R_(t)=2.8 min.

Nonpolar Diastereoisomer

Yield: 16 mg (1%, based on the stage 2 employed), yellow oil

¹H-NMR (CDCl₃): 1.43-1.82 (m, 8H); 2.12 (s, 6H); 2.51 (d, 2H, J=13.8Hz); 2.63 (dd, 1H, J=9.5 and 13.6 Hz); 2.97 (dd, 1H, J=3.4 and 13.6 Hz);3.70 (m, 1H); 6.87 (dd, 1H, J=1.1 and 3.4 Hz); 7.03 (dd, 1H, J=3.6 and5.1 Hz); 7.20-7.27 (m, 4H); 7.30-7.36 (m, 2H).

LC-MS (method 1): [M+H]⁺: m/z=330.3, R_(t)=3.3 min.

Example 8 1-(4-Butyl-4-dimethylaminocyclohexyl)-2-phenylethanol

In an analogous procedure to Example 6 and 7 using stage 4 and replacingthienylmagnesium bromide by butylmagnesium bromide in stage 5, Example 8was obtained.

Stage 5{1-Butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine

A 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (4.62 ml,9.25 mmol) was added dropwise to a solution of1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile(1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with iceand under an argon atmosphere. The mixture was stirred at roomtemperature for 48 h and thereafter water and saturated ammoniumchloride solution (10 ml of each) were added. The phases were separatedand the aqueous phase was extracted with diethyl ether (3×10 ml). Thecombined organic phases were dried with sodium sulfate and concentratedi. vac.

Yield: 1.12 g, yellowish oil.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals.

The product is a mixture of diastereoisomers.

Stage 6 1-(4-Butyl-4-dimethylaminocyclohexyl)-2-phenylethanol

2 M hydrochloric acid (20 ml) was added to a solution of{1-butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine(1.09 g, 2.90 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixturewas stirred at room temperature for 3 d. The tetrahydrofuran was removedi. vac. and the acid aqueous solution was extracted with diethyl ether(3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxidesolution. The alkaline phase was extracted with methylene chloride (4×10ml). The combined organic phases were dried with sodium sulfate andconcentrated i. vac. The crude product (646 mg) was purified by flashchromatography with methylene chloride/methanol (9:1→8:2→0:1). Theproduct obtained in this way was in the form of the hydrochloride. Itwas taken up in methylene chloride and the suspension was washed withsaturated potassium carbonate solution. The organic phase was dried withsodium sulfate and concentrated i. vac.

Yield: 306 mg (35%, based on the stage 2 employed), yellowish oil

¹H-NMR (DMSO-d₆): 0.86 (t, 3H, J=7.0 Hz); 1.45-1.58 (m, 13H); 1.66-1.75(m, 2H); 2.13 (s, 6H); 2.52 (dd, 1H, J=8.5 and 13.3 Hz, partlyoverlapped by the DMSO signal); 2.72 (dd, 1H, J=4.1 and 13.6 Hz); 3.38(m, 1H); 4.26 (d, 1H, J=6.0 Hz); 7.10-7.30 (m, 5H).

¹³C-NMR (DMSO-d₆): 13.9; 21.6; 23.4; 23.5; 26.4; 30.8; 32.0; 32.1; 36.8;40.6; 43.0; 55.5; 75.3; 125.4; 127.8; 129.1; 140.3.

LC-MS (method 7): [M+H]⁺: m/z=304.5, R_(t)=2.9 min.

Example 91-[4-Dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

In an analogous procedure to Example 6 and 7 using stage 4 and replacingthienylmagnesium bromide by 3-methoxyphenylmagnesium bromide in stage 5,Example 9 was obtained.

Stage 5[4-[1-(1-Ethoxy-ethoxy)-2-phenylethyl]-1-(3-methoxyphenyl)cyclohexyl]dimethylamine

A 1 M solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran(9.25 ml, 9.25 mmol) was added dropwise to a solution of1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile(1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with iceand under an argon atmosphere. The mixture was stirred at roomtemperature for 48 h and thereafter water and saturated ammoniumchloride solution (10 ml of each) were added. The phases were separatedand the aqueous phase was extracted with diethyl ether (3×10 ml). Thecombined organic phases were dried with sodium sulfate and concentratedi. vac.

Yield: 1.56 g, yellowish oil.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals.

The product is a mixture of diastereoisomers.

Stage 61-[4-Dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

2 M hydrochloric acid (20 ml) was added to a solution of WW561 (1.54 g,3.61 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture wasstirred at room temperature for 2 d. The tetrahydrofuran was removed i.vac. and the acid aqueous solution was extracted with diethyl ether(3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxidesolution. The alkaline aqueous phase was extracted with methylenechloride (4×10 ml). The combined organic phases were dried with sodiumsulfate and concentrated i. vac. The crude product (670 mg) was purifiedby flash chromatography with cyclohexane/ethyl acetate (3:2)→methylenechloride/methanol (9:1).

Yield: 163 mg (15%, based on stage 3), white solid

Melting point: 75° C.

¹H-NMR (DMSO-d₆): 1.15-1.52 (m, 7H); 1.95 (s, 6H); 2.52-2.68 (m, 3H);2.77 (dd, 1H, J=3.7 and 13.6 Hz); 3.45 (m, 1H); 3.74 (s, 3H); 4.33 (d,1H, J=6.1 Hz); 6.78-6.84 (m, 2H); 6.89 (d, 1H, J=7.9 Hz); 7.11-7.30 (m,6H).

¹³C-NMR (DMSO-d₆): 22.2; 24.2; 32.8; 32.9; 37.6; 40.5; 42.9; 58.2; 75.0;110.9; 112.9; 118.8; 125.3; 127.7; 127.9; 129.3; 140.5; 141.5; 158.6.

A further fraction with impure product (350 mg) was purified again byflash chromatography with methylene chloride/methanol (95:5), as aresult of which a further 90 mg of1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol wereobtained (8%, based on stage 3), white solid.

Melting point: 72° C.

Example 101-[4-Dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

Stage 1 4-Dimethylamino-4-(3-methoxyphenyl)cyclohexanecarbonitrile

A solution of 4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexanone (2.47g, 10 mmol) and tosylmethyl isocyanide (2.54 g, 13 mmol) in anhydrous1,2-dimethoxyethane (40 ml) and anhydrous ethanol (2 ml) was cooled to−30° C. A solution of potassium tert-butylate (2.70 g, 24 mmol) inanhydrous tetrahydrofuran (20 ml) was then added dropwise such that theinternal temperature did not rise above 5° C. The mixture was stirred at0° C. for 1 h, at room temperature for 24 h and then under reflux for 5h. The reaction mixture was cooled to room temperature and filtered. Theresidue on the filter was washed with 1,2-dimethoxyethane. The filtratewas concentrated i. vac., the residue was taken up in diethyl ether andthe solution was washed with water (3×20 ml) and saturated sodiumchloride solution (20 ml). The organic phase was dried with sodiumsulfate and concentrated i. vac. The crude product (1.76 g) was purifiedby flash chromatography with ethyl acetate and then ethylacetate/methanol (9:1→8:2).

Nonpolar Diastereoisomer

Yield: 401 mg (15%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.60-1.90 (m, 6H); 1.94 (s, 6H); 2.22-2.34 (m, 2H);2.81 (m, 1H); 3.74 (s, 3H); 6.78-6.90 (m, 3H); 7.27 (t, 1H, J=7.9 Hz).

¹³C-NMR (DMSO-d₆): 24.7; 26.3; 30.5; 37.4; 54.9; 58.7; 111.3; 113.2;119.3; 122.9; 128.4; 139.2; 158.8.

LC-MS (method 8): [M+H]⁺: m/z=259.3, R_(t)=0.9 min.

Polar Diastereoisomer

Yield: 505 mg (19%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.33-1.52 (m, 2H); 1.92 (s, 6H); 1.93-2.18 (m, 6H);2.92 (m, 1H); 3.76 (s, 3H); 6.80-6.94 (m, 3H); 7.30 (t, 1H, J=7.9 Hz).

¹³C-NMR (DMSO-d₆): 24.9; 26.4; 30.3; 37.7; 54.8; 59.2; 111.4; 113.6;119.4; 122.8; 128.4; 138.7; 158.8.

LC-MS (method 8): [M+H]⁺: m/z=259.2, R_(t)=1.0 min.

Stage 21-[4-Dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanone

A 2 M solution of benzylmagnesium chloride in tetrahydrofuran (1.4 ml,2.8 mmol) was added to a solution of the polar diastereoisomer (240 mg,0.9 mmol) in anhydrous tetrahydrofuran (5 ml), while cooling with ice,and the mixture was stirred at room temperature for 3 d. Saturatedammonium chloride solution (8 ml) and water (5 ml) were added to thereaction mixture. The solvent was removed i. vac. and the aqueoussuspension was extracted with diethyl ether (3×20 ml). The combinedorganic phases were dried with sodium sulfate and concentrated i. vac.The crude product was purified by flash chromatography with methylenechloride/methanol (95.5).

Yield: 120 mg (36%), yellowish oil.

¹H-NMR (CDCl₃): 1.33-1.46 (m, 2H); 1.72 (t, 2H, J=14.5 Hz); 1.87 (d, 2H,J=11.1 Hz); 2.13 (s, 6H); 2.56 (m, 1H); 2.70 (d, 2H, J=12.5 Hz); 3.69(s, 2H); 3.85 (s, 3H); 6.82-6.94 (m, 4 Hz); 7.16 (d, 1H, J=7.1 Hz);7.22-7.38 (m, 4H).

Stage 31-[4-Dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

Sodium borohydride (24 mg, 0.6 mmol) was added to a solution of theproduct from stage 2 (112 mg, 0.3 mmol) in anhydrous methanol (5 ml) at0° C. and the mixture was stirred at room temperature for 3 h. Furthersodium borohydride (12 mg, 0.3 mmol) was then added and the mixture wasstirred at room for a further 2 h. Water (20 ml) was added to themixture. The solvent was removed i. vac. and the aqueous suspension wasextracted with ethyl acetate (3×10 ml). The combined organic phases weredried with sodium sulfate and concentrated i. vac. The crude product (76mg) was purified by flash chromatography (10 g, 20×1.1 cm) withmethylene chloride/methanol [(95.5)+1% ammonia solution (30% in H₂O)].

Yield: 57 mg (50%), yellowish solid

Melting point: 120° C.

¹H-NMR (DMSO-d₆): 0.84-1.12 (m, 2H); 1.18-1.58 (m, 6H); 1.72 (d, 1H,J=12.5 Hz); 1.91 (s, 6H); 2.40-2.50 (m, 1H); 2.54-2.70 (m, 2H); 3.26 (m,1H); 3.75 (s, 3H); 4.20 (d, 1H, J=6.0 Hz); 6.79-6.92 (m, 3H); 7.10-7.33(m, 6H).

¹³C-NMR (DMSO-d₆): 23.5; 25.9; 32.5; 32.7; 37.9; 40.7; 42.9; 61.1; 74.6;110.7; 114.4; 120.3; 125.3; 127.8; 128.4; 129.1; 138.4; 140.1; 158.9.

Example 111-(4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-(5-(phenylsulfonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)ethanol

Stage 1 1,3,4,9-Tetrahydro-β-carboline-2-carboxylic acid benzyl ester

A solution of N-(benzyloxycarbonyloxy)succinimide (9.61 g, 38.6 mmol) inanhydrous tetrahydrofuran (30 ml) was added to a suspension of2,3,4,9-tetrahydro-1H-β-carboline (4.43 g, 25.7 mmol) and4-N,N-dimethylaminopyridine (266 mg) in anhydrous tetrahydrofuran (30ml), while cooling with ice. The suspension was stirred at roomtemperature for 16 h and the tetrahydrofuran was then removed i. vac.The residue was dissolved in ethyl acetate (20 ml) and the solution waswashed with water (2×20 ml). The organic phase was dried with sodiumsulfate and concentrated i. vac. The crude product (11.0 g) was purifiedby flash chromatography with cyclohexane/ethyl acetate (4:1).

Yield: 6.64 g (84%), white solid

¹H-NMR (DMSO-d₆): 2.71 (t, 2H, J=5.6 Hz); 3.76 (t, 2H, J=5.3 Hz); 4.64(br s, 2H); 5.14 (s, 2H); 6.96 (ddd, 1H, J=8.0, 7.1 and 1.1 Hz); 7.04(ddd, 1H, J=8.2, 7.1 and 1.2 Hz); 7.25-7.44 (m, 7H); 10.78 and 10.84 (2s, 1H).

Stage 2 9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carboline-2-carboxylicacid benzyl ester

Powdered sodium hydroxide (1.73 g, 43.3 mmol) and tetra-n-butylammoniumhydrogen sulfate (111 mg) were added to a solution of the product fromstage 1 (6.61 g, 21.6 mmol) in anhydrous methylene chloride (100 ml) andthe mixture was stirred at room temperature for 1 h. Benzenesulfonylchloride (4.21 g, 3.07 ml, 23.8 mmol) was added to the suspension, whilecooling with ice. The mixture was stirred at room temperature for 16 hand water and methylene chloride (50 ml of each) were then added. Theorganic phase was separated off and washed with sodium chloride solution(40 ml). The organic phase was dried with sodium sulfate andconcentrated i. vac. The residue was purified by flash chromatographywith cyclohexane/ethyl acetate (4:2).

Yield: 5.66 g (58%), white solid

Melting point: 153° C.

¹H-NMR (DMSO-d₆): 2.67 (t, 2H, J=5.5 Hz); 3.73 (t, 2H, J=4.7 Hz); 4.97(br s, 2H); 5.16 (s, 2H); 7.26 (dt, 1H, J=7.4 and 1.0 Hz); 7.31-7.94 (m,12H); 8.01 (br d, J=8.1 Hz).

Stage 3 9-Benzenesulfonyl-2,3,4,9-tetrahydro-1H-β-carboline

33% hydrogen bromide in glacial acetic acid (20.7 ml) was added to asuspension of the product from stage 2 (4.14 g, 9.27 mmol) in glacialacetic acid (20.7 ml) and the mixture was stirred at room temperaturefor 1 h. The mixture was poured into diethyl ether (500 ml). Thehydrobromide which had precipitated out was filtered off with suction,washed with diethyl ether and dried over potassium hydroxide in adesiccator. Saturated potassium carbonate solution (100 ml) was added tothe salt (3.60 g) and the resulting mixture was extracted with methylenechloride (3×25 ml). The combined organic phases were dried with sodiumsulfate and concentrated i. vac.

Yield: 2.51 g (86%), white solid

Melting point: 190-195° C.

¹H-NMR (DMSO-d₆): 2.53 (t, 2H, J=5.5 Hz); 2.91 (t, 2H, J=5.5 Hz); 4.11(s, 2H); 7.20-7.33 (m, 2H); 7.40-7.43 (m, 1H); 7.52-7.60 (m, 2H);7.62-7.70 (m, 1H); 7.84-7.90 (m, 2H); 7.96-8.04 (m, 1H).

Stage 42-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol

Calcium trifluoromethanesulfonate (1.22 g, 3.60 mmol) was added to asolution of the product from stage 3 (2.51 g, 8.05 mmol) and8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.34 g, 7.30 mmol) in anhydroustetrahydrofuran (50 ml) and the mixture was stirred at room temperaturefor 48 h. The tetrahydrofuran was removed i. vac. The residue was takenup in methylene chloride (40 ml) and the mixture was washed with 25%potassium carbonate solution (2×25 ml). The organic phase was dried withsodium sulfate and concentrated i. vac. The crude product (4.31 g) waspurified by flash chromatography with cyclohexane/ethyl acetate (1:2).

Yield: 2.33 g (64%), white solid

Melting point: 158° C.

¹H-NMR (DMSO-d₆): 1.22-1.48 (m, 5H); 1.57 (s, 1H); 1.62-1.78 (m, 3H);2.48-2.68 (m, 4H); 2.72-2.90 (m, 2H); 3.51 (m, 1H); 3.83 (s, 4H); 3.95(d, 1H, J=17.0 Hz); 4.03 (d, 1H, J=17.0 Hz); 4.38 (d, 1H, J=4.4 Hz);7.25 (dt, 1H, J=7.3 and 1.2 Hz); 7.31 (ddd, 1H, J=8.4, 7.3 and 1.5 Hz);7.40-7.45 (m, 1H); 7.51-7.60 (m, 2H); 7.64-7.71 (m, 1H); 7.82-7.89 (m,2H); 7.99-8.03 (m, 1H).

Stage 54-[2-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-hydroxyethyl]cyclohexanone

2 M hydrochloric acid (30 ml) was added to a solution of the productfrom stage 4 (748 mg, 1.50 mmol) in tetrahydrofuran (30 ml) and themixture was stirred at room temperature for 16 h. The mixture wasrendered alkaline with 4 M sodium hydroxide solution and extracted withethyl acetate (3×35 ml). The combined organic phases were dried withsodium sulfate and concentrated i. vac.

Yield: 658 mg (96%), beige-coloured solid

Melting point: 174° C.

¹H-NMR (DMSO-d₆): 1.40-1.64 (m, 2H); 1.76-1.98 (m, 2H); 2.02 (m, 1H);2.15-2.26 (m, 2H); 2.27-2.45 (m, 2H); 2.54-2.70 (m, 4H); 2.77-2.93 (m,2H); 3.64 (m, 1H); 3.98 (d, 1H, J=17.0 Hz); 4.06 (d, 1H, J=17.0 Hz);4.56 (d, 1H, J=4.4 Hz); 7.25 (dt, 1H, J=7.3 and 1.1 Hz); 7.32 (ddd, 1H,J=8.6, 7.3 and 1.4 Hz); 7.44 (m, 1H); 7.52-7.60 (m, 2H); 7.67 (m, 1H);7.83-7.89 (m, 2H); 8.02 (br d, 1H, J=7.8 Hz).

LC-MS (method 7): [M+H]⁺: m/z=453.2, R_(t)=2.7 min.

Stage 64-[2-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(tert-butyldimethylsilanyloxy)ethyl]cyclohexanone

A solution of the product from stage 6 (553 mg, 1.22 mmol), imidazole(250 mg, 3.66 mmol) and tert-butyldimethylchlorosilane (275 mg, 1.83mmol) in anhydrous N,N-dimethylformamide (20 ml) was stirred at roomtemperature for 48 h. The reaction mixture was concentrated i. vac. 25%potassium carbonate solution (30 ml) was added to the residue and themixture was extracted with methylene chloride (3×35 ml). The combinedorganic phases were dried with sodium sulfate and concentrated i. vac.The crude product (1.3 g) was purified by flash chromatography (85 g,20×3.8 cm) with cyclohexane/ethyl acetate (2:1).

Yield: 588 mg (85%), white solid

Melting point: 150-152° C.

¹H-NMR (DMSO-d₆): 0.03 (s, 3H); 0.04 (s, 3H); 0.85 (s, 9H); 1.44-1.66(m, 2H); 1.86-2.06 (m, 3H); 2.14-2.25 (m, 2H); 2.28-2.47 (m, 2H);2.55-2.70 (m, 4H); 2.71-2.92 (m, 2H); 3.83 (m, 1H); 3.89 (d, 1H, J=16.8Hz); 4.00 (d, 1H, J=16.8 Hz); 7.26 (dt, 1H, J=7.3 and 1.2 Hz); 7.32(ddd, 1H, 8.6, 7.3 and 1.4 Hz); 7.42-7.48 (m, 1H); 7.52-7.60 (m, 2H);7.64-7.72 (m, 1H); 7.80-7.88 (m, 2H); 8.00-8.06 (m, 1H).

Stage 74-[2-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(tert-butyldimethylsilanyloxy)ethyl]-1-dimethylamino-cyclohexanecarbonitrile

40% aqueous dimethylamine solution (596 μl, 4.73 mmol) was added to amixture of 4 M hydrochloric acid (256 μl) and methanol (153 μl), whilecooling with ice. A solution of the product from stage 6 (557 mg, 0.98mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was added to themixture. Potassium cyanide (153 mg, 2.36 mmol) and water (2 ml) werethen added. The suspension was stirred at room temperature overnight andthereafter diluted with water (20 ml). The mixture was extracted withdiethyl ether (5×20 ml). The combined organic phases were dried withsodium sulfate and concentrated i. vac.

Yield: 609 mg (100%), yellowish oil.

The product is a diastereoisomer mixture.

¹H-NMR (DMSO-d₆): The spectrum contains all the expected signals.

Stage 8[4-[2-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(tert-butyldimethylsilanyloxy)ethyl]-1-(3-fluorophenyl)cyclohexyl]dimethylamine

A 1 M solution of 3-fluorophenylmagnesium bromide in tetrahydrofuran(2.5 ml, 2.5 mmol) was added to a solution of the product from stage 7(521 mg, 0.84 mmol) in anhydrous tetrahydrofuran (20 ml), while coolingwith ice and under argon, and the mixture was stirred at roomtemperature for 2 d. Saturated ammonium chloride solution and water (10ml of each) were then added to the reaction mixture and the phases wereseparated. The aqueous phase was extracted with diethyl ether (2×30 ml).The combined organic phases were dried with sodium sulfate andconcentrated i. vac. The residue (491 mg) was purified by flashchromatography with cyclohexane/ethyl acetate (4:1), as a result ofwhich the product (211 mg) still contaminated with 3-fluorophenol wasobtained. This was purified again by flash chromatography withcyclohexane/tert-butyl methyl ether (4:1).

Yield: 149 mg (25%), white solid

¹H-NMR (DMSO-d₆): 0.01 (s, 3H); 0.04 (s, 3H); 0.88 (s, 9H); 1.15-1.80(m, 7H); 1.92 (s, 6H); 2.56-2.56 (m, 6H); 2.56-2.95 (m, 2H); 3.65-3.73(m, 1H); 3.86 (d, 1H, J=16.9 Hz); 3.99 (d, 1H, J=17.0 Hz); 7.00-7.15 (m,2H); 7.20-7.45 (m, 5H); 7.50-7.59 (m, 2H); 7.62-7.70 (m, 1H); 7.80-7.87(m, 2H); 8.01 (d, 1H, J=8.2 Hz).

¹³C-NMR (DMSO-d₆): −5.1; −4.9; −4.0; −3.8; 17.9; 20.5; 24.1; 25.8; 25.9;32.6; 32.7; 37.4; 49.7; 51.6; 58.3; 61.3; 71.3; 74.1; 111.6 (d, J=22Hz); 112.6 (d, J=21 Hz); 113.1; 113.7; 117.1; 118.6; 120.7 (br); 122.4;122.5; 123.6; 124.4; 126.0; 128.8 (d, J=8 Hz); 129.3; 129.8; 132.9;134.5; 135.3; 137.4; 143.1 (d, J=6 Hz); 161.9 (d, J=242 Hz).

LC/MS (method 8): [M+H]⁺: m/z=691.4, R_(t)=4.2 min.

Stage 92-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]ethanol

2 M hydrochloric acid (20 ml) was added to a solution of the productfrom stage 8 (176 mg, 0.255 mmol) in tetrahydrofuran (20 ml) and themixture was stirred at room temperature for 1 d. The reaction mixturewas then stirred at 50° C. for 15 h and then at room temperature for afurther 16 h. The mixture was then rendered alkaline with 2 M sodiumhydroxide solution (30 ml) and the phases were separated. The aqueousphase was extracted with diethyl ether (3×10 ml). The combined organicphases were dried with sodium sulfate and concentrated i. vac. The crudeproduct 151 mg) was purified by flash chromatography with methylenechloride/methanol (97:3).

Yield: 35 mg (22%), colourless oil

¹H-NMR (CDCl₃): 1.35-1.78 (m, 7H); 1.85 (br d, 1H, J=12.4 Hz); 2.04 (s,6H); 2.48-2.66 (m, 3H); 2.50-2.86 (m, 4H); 3.05 (m, 1H); 3.65 (t, 1H,J=7.8 Hz); 4.02 (d, 1H, J=16.4 Hz); 4.13 (d, 1H, J=16.4 Hz); 6.95 (t,1H, J=8.1 Hz); 7.01 (dd, 1H, J=11.5 and 1.4 Hz); 7.09 (d, 1H, J=7.5 Hz);7.20-7.46 (m, 6H); 7.52 (m, 1H); 7.77 (m, 2H); 8.12 (d, 1H, J=8.1 Hz).

¹³C-NMR (CDCl₃): 20.8; 23.2; 23.8; 32.9; 37.6; 41.9; 49.5; 51.3; 58.7;60.3; 70.1; 113.1 (d, J=20 Hz); 113.6 (d, J=21 Hz); 114.2; 117.3; 118.2;122.4; 123.6; 124.3; 126.2; 128.5 (d, J=8 Hz); 129.3; 129. 6; 132.6;133.6; 136.1; 138.7; 143.0 (br); 162 (d, J=245 Hz).

LC-MS (method 7): [M+H]⁺: m/z=576.3, R_(t)=2.4 min.

Example 122-(1,3-Dihydroisoindol-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

Stage 12-(1,3-Dihydroisoindol-2-yl)-1-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol

A solution of 8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.41 g, 7.66 mmol),isoindoline (1.00 g, 8.43 mmol) and calcium trifluoromethanesulfonate(1.29 g, 3.8 mmol) in anhydrous acetonitrile (60 ml) was stirred at roomtemperature overnight. The solvent was then concentrated in vacuo. Theresidue was taken up in ethyl acetate (50 ml) and the solution waswashed with 25% potassium carbonate solution (3×50 ml). The aqueousphase was extracted with ethyl acetate (3×40 ml) and the combinedorganic phases were dried with sodium sulfate and concentrated in vacuo.

Yield: 2.04 g (88%), beige-coloured solid

¹H-NMR (DMSO-d₆): 1.24-1.48 (m, 5H); 1.59 (br s, 1H); 1.64-1.74 (m, 3H);2.56 (dd, 1H, J=7.4, 12.2 Hz); 2.70 (dd, 1H, J=4.7, 12.2 Hz); (m, 2H);3.44 (m, 1H); 3.83 (s, 4H); 3.83-3.94 (m, 4H); 4.30 (d, 1H, J=4.4 Hz);7.15-7.26 (m, 4 H).

Stage 2 4-[2-(1,3-Dihydroisoindol-2-yl)-1-hydroxyethyl]cyclohexanone

2 M hydrochloric acid (19 ml) was added to a solution of2-(1,3-dihydroisoindol-2-O-1-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol (2.05g, 6.74 mmol) in acetone (60 ml) and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo,the residue was rendered alkaline with 2 M sodium hydroxide solution andthe solution was extracted with methylene chloride (3×40 ml). Thecombined organic phases were dried with sodium sulfate and concentratedin vacuo. The crude product (1.67 g) was purified by flashchromatography with ethyl acetate/methanol (9:1).

Yield: 1.12 g (64%), beige-coloured solid

Melting point: 136° C.

¹H-NMR (DMSO-d₆): 1.40-1.68 (m, 2H); 1.82-2.10 (m, 3H); 2.14-2.24 (m,2H); 2.28-2.46 (m, 2H); 2.70 (dd, 1H, J=7.1, 12.3 Hz); 2.77 (dd, 1H,J=5.2 Hz); 3.58 (m, 1H); 3.85-3.97 (m, 4H); 4.54 (br s, 1H); 7.15-7.25(m, 4H).

Stage 34-[2-(1,3-Dihydroisoindol-2-yl)-1-hydroxyethyl]-1-dimethylaminocyclohexanecarbonitrile

40% aqueous dimethylamine solution (1.72 ml, 12.5 mmol) was added to 4 Mhydrochloric acid (706 μl), cooled to 0, in methanol (785 μl). Asolution of 4-[2-(1,3-dihydroisoindol-2-yl)-1-hydroxyethyl]cyclohexanone(732 mg, 2.82 mmol) in methanol (4 ml) and tetrahydrofuran (6 ml) wasthen added. Potassium cyanide (445 mg, 6.67 mmol) was then added to themixture and the mixture was stirred at room temperature overnight.Thereafter, water (80 ml) was added to the reaction mixture and themixture was extracted with diethyl ether (3×20 ml). The combined organicphases were dried with sodium sulfate and concentrated in vacuo.

Yield: 672 mg (76%), white solid

¹H-NMR (DMSO-d₆): 1.20-1.50 (m, 7H); 1.60-1.90 (m, 2H); 2.22 and 2.33 (2s, 6H); 2.63-2.75 (m, 2H); 3.45 (m, 1H); 3.82-3.94 (m, 4H); 4.36 and4.45 (2 d, 1H, J=in each case 4.7 Hz); 7.15-7.24 (m, 4H).

A diastereoisomer mixture in the ratio of approx. 4.5:1 was obtained.

Stage 42-(1,3-Dihydroisoindol-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

A solution of4-[2-(1,3-dihydroisoindol-2-yl)-1-hydroxyethyl]-1-dimethylaminocyclohexanecarbonitrile(666 mg, 2.12 mmol) in anhydrous tetrahydrofuran (30 ml) was addeddropwise to a 2 M solution of phenylmagnesium chloride intetrahydrofuran (4.25 ml, 8.49 mmol), while cooling with ice, and themixture was stirred at room temperature overnight. Saturated ammoniumchloride solution and water (10 ml of each) were then added dropwise tothe mixture, while cooling with ice. The tetrahydrofuran was distilledoff in vacuo and the residue was extracted with diethyl ether (3×30 ml).The combined organic phases were dried with sodium sulfate andconcentrated in vacuo. The crude product (761 mg) was purified by flashchromatography with chloroform/methanol (9:1). Renewed flashchromatography with chloroform (saturated with 25% aqueous ammoniasolution)/methanol (95:5) gave a yield of 83 mg (10%) of beige-colouredsolid.

Melting point: 130-135° C.

¹H-NMR (CDCl₃): 1.26 (s, 1H); 1.40-1.90 (m, 7H); 2.05 (s, 6H); 2.58-2.70(m, 2H); 2.79 (dd, 1H, J=10.2, 11.8 Hz); 2.84 (dd, 1H, J=3.5, 11.8 Hz);3.63 (m, 1H); 3.93 (d, 2H, J=11.1 Hz); 4.12 (d, 2H, J=11.1 Hz);7.21-7.29 (m, 5H); 7.30-7.39 (m, 4H).

A diastereoisomer mixture in the ratio of approx. 4:1 was obtained.

Example 13 and Example 14(1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol, NonpolarDiastereoisomer)(1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol, PolarDiastereoisomer)

Stage 1 8-Oxiranyl-1,4-dioxaspiro[4.5]decane

A 60% strength dispersion of sodium hydride in mineral oil (1.78 g,44.59 mmol) was taken up in dimethylsulfoxide (25 ml), andtrimethylsulfoxonium iodide (9.80 g, 44.6 mmol) was added. The mixturewas stirred at room temperature for 45 min. A solution of1,4-dioxaspiro[4,5]decane-8-carbaldehyde (7.59 g, 44.6 mmol) indimethylsulfoxide (20 ml) was then added to the mixture. The reactionmixture was stirred at 60° C. for 18 h. After cooling, the mixture waspoured into water (100 ml) and extracted with diethyl ether (4×20 ml).The combined organic phases were dried with sodium sulfate andconcentrated in vacuo. The crude product (4.64 g) was purified by flashchromatography with cyclohexane/ethyl acetate (4:1).

Yield: 1.09 g (13%), colourless oil

¹H-NMR (DMSO-d₆): 1.10-1.85 (m, 8H); 2.50 (2H, overlapped by the DMSOsignal); 2.64 (dd, 1H, J=5.0, 4.0 Hz); 2.71 (ddd, 1H, J=6.6, 4.0, 2.7Hz); 3.84 (s, 4H).

The following product batches were obtained in an analogous manner:

-   a) from 1.16 g of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde 247 mg,    20% of th.-   b) from 2.99 g of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde 560 mg,    17% of th.-   c) from 7.6 g of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde 7.34 g,    17% of th., this batch containing large amounts of methylene    chloride and cyclohexane. The content of product was at most approx.    30% of th.

Stage 2 1-(1,4-Dioxaspiro[4.5]dec-8-yl)-2-phenoxyethanol

A 60% strength dispersion of sodium hydride in mineral oil (834 mg, 20.7mmol) was taken up in anhydrous N,N-dimethylformamide (10 ml), andphenol (1.96 g, 20.8 mmol) was added. The mixture was stirred at roomtemperature for 15 min and a solution of8-oxiranyl-1,4-dioxaspiro[4.5]decane (2.62 g, content approx. 30%,approx. 4 mmol) in N,N-dimethylformamide (6 ml) was then added. Thereaction mixture was stirred at 120° C. for 5.5 h and then cooled toroom temperature, water (1 ml) was added and the mixture wasconcentrated in vacuo. Toluene was repeatedly added to the residue andthe mixture was concentrated again in vacuo each time. The crude product(2.9 g) was purified by flash chromatography (200 g, 20×5.6 cm) withcyclohexane/ethyl acetate (4:1).

Yield: 1.01 g (90%), colourless oil

¹H-NMR (DMSO-d₆): 1.30-1.80 (m, 9H); 3.59 (m, 1H); 3.82-3.88 (s, 4H,overlapped by dd, 1H); 3.93 (dd, 1H, J=4.2, 9.9 Hz); 4.79 (d, 1H, J=5.4Hz); 6.88-6.95 (m, 3H); 7.24-7.30 (m, 2H).

Stage 3 4-(1-Hydroxy-2-phenoxyethyl)cyclohexanone

2 M hydrochloric acid was added to a solution of1-(1,4-dioxaspiro[4.5]dec-8-yl)-2-phenoxyethanol (1.25 g, 4.5 mmol) inacetone (30 ml) and the mixture was stirred at room temperature for 48h. The acetone was removed in vacuo, the pH of the aqueous residue wasrendered alkaline with 2 M sodium hydroxide solution and the aqueousresidue was extracted with methylene chloride (4×20 ml). The combinedorganic phases were dried with sodium sulfate and concentrated in vacuo.

Yield: 928 mg (88%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.45-1.65 (m, 2H); 1.88-2.13 (m, 3H); 2.15-2.26 (m,2H); 2.31-2.45 (m, 2H); 3.72 (m, 1H); 3.90 (dd, 1H, J=6.2, 9.9 Hz); 3.99(dd, 1H, J=4.4, 9.9 Hz); 4.96 (d, 1H, J=5.4 Hz); 6.90-6.98 (m, 3H);7.25-7.32 (m, 2H).

Stage 4 4-[1-(1-Ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanone

Pyridinium tosylate (15 mg, 0.06 mmol) and ethyl vinyl ether (339 mg,450 μl, 4.70 mmol) were added to a solution of4-(1-hydroxy-2-phenoxyethyl)cyclohexanone (919 mg, 3.92 mmol) inanhydrous methylene chloride (20 ml) and the mixture was stirred at roomtemperature overnight. Methylene chloride (20 ml) was then added to themixture and the mixture was washed with water, 5% strength sodiumbicarbonate solution and saturated sodium chloride solution (50 ml ofeach). The organic phase was dried with sodium sulfate and concentratedin vacuo.

The crude product (1.09 g) was purified by flash chromatography withcyclohexane/ethyl acetate (4:1).

Yield: 929 mg (77%), colourless oil

¹H-NMR (DMSO-d₆): 1.02-1.13 (m, 3H); 1.21 (dd, 3H, J=5.2, 9.1 Hz);1.44-1.70 (m, 3H); 1.90-2.30 (m, 4H); 2.32-2.47 (m, 2H); 3.38-3.64 (m,2H); 3.71-3.88 (m, 1H); 3.94-4.15 (m, 2H); 4.80 and 4.90 (2 q, 1H, J=5.3Hz); 6.90-6.94 (m 3H); 7.29 (t, 2H, J=8.0 Hz).

The product was obtained as a diastereoisomer mixture.

Stage 51-Dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile

40% aqueous dimethylamine solution (1.73 ml, 13.7 mmol) was added to amixture of 4 M hydrochloric acid (747 μl) and methanol (448 μl), whilecooling with ice, and the mixture was added to4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanone (880 mg, 2.87 mmol),before potassium cyanide (448 mg, 6.88 mg) was added. Tetrahydrofuran (3ml) was also added for solubilization. The reaction mixture was stirredat room temperature for 6 h, water (50 ml) was then added and themixture was extracted with diethyl ether (4×30 ml). The combined organicphases were concentrated in vacuo, the residue was taken up in methylenechloride (30 ml) and the mixture was washed with water (30 ml). Theorganic phase was dried with sodium sulfate and concentrated in vacuo.

Yield: 877 mg (84%), colourless oil

¹H-NMR (DMSO-d₆): 1.00-1.12 (m, 3H); 1.16-1.24 (m, 3H); 1.30-2.00 (m,8H); 2.10-2.30 (m, 7H); 3.40-3.70 (m, 3H); 4.00-4.10 (m, 2H); 4.74-4.90(m, 1H); 6.90-6.99 (m, 3H); 7.25-7.32 (m, 2H).

The product is in the form of a mixture of diastereoisomers.

Stage 6{4-[1-(1-Ethoxy-ethoxy)-2-phenoxyethyl]-1-phenylcyclohexyl}dimethylamine

A solution of1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile(871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml) was addeddropwise to a 2 M solution of phenylmagnesium chloride intetrahydrofuran (3.6 ml, 7.3 mmol), while cooling with ice. The mixturewas stirred at room temperature overnight and saturated ammoniumchloride solution and water (5 ml of each) were then added. The phaseswere separated and the aqueous phase was extracted with diethyl ether(3×20 ml). The combined organic phases were dried with sodium sulfateand concentrated in vacuo.

Yield: 946 mg (99%), yellowish oil.

¹H-NMR (DMSO-d₆): 0.90-1.26 (m, 6H); 1.26-1.80 (m, 9H); 1.93 (s, 6H);2.61-2.71 (m, 1H); 3.40-3.69 (m, 2H); 3.93-4.14 (m, 2H); 4.71-4.92 (m,1H); 6.70-7.70 (m, 10H).

The product was obtained as a diastereoisomer mixture.

Stage 7 1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol

2 M hydrochloric acid (10 ml) was added to a solution of{4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]-1-phenylcyclohexyl}dimethylamine(892 mg, 2.16 mmol) in acetone (30 ml) and the mixture was stirred atroom temperature overnight. The pH of the mixture was then renderedalkaline with 0.5 M sodium hydroxide solution and the mixture wassubsequently extracted with methylene chloride (3×30 ml). The combinedorganic phases were dried with sodium sulfate and concentrated in vacuo.The crude product (1.26 g) was purified by flash chromatography withethyl acetate/methanol (9:1→0:1).

1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol (NonpolarDiastereoisomer)

Yield: 317 mg (43%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.22-1.38 (m, 2H); 1.40-1.74 (m, 5H); 1.92 (s, 6H);2.58-2.74 (m, 2H); 3.56-3.65 (m, 1H); 3.88 (dd, 1H, J=10.0, 6.3 Hz);3.98 (dd, 1H, J=10.0, 4.0 Hz); 4.78 (d, 1H, J=5.5 Hz); 6.88-6.97 (m,3H); 7.18-7.37 (m, 7H).

1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol (PolarDiastereoisomer)

Yield: 41 mg (5%), yellowish solid

Melting point: 145-147° C.

¹H-NMR (DMSO-d₆): 0.80-1.10 (m, 2H); 1.38-1.54 (m, 4H); 1.72 (br d, 1H,J=12.8 Hz); 1.89 (s, 6H); 2.58-2.74 (m, 2H); 3.40-3.52 (m, 1H); 3.77(dd, 1H, J=9.9, 6.1 Hz); 3.84 (dd, 1H, J=9.9, 4.4 Hz); 4.67 (br s, 1H);6.84-6.92 (m, 3H); 7.20-7.40 (m, 7H).

Example 15 2-Benzyloxy-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

Stage 1

By replacing phenol by benzyl alcohol in Example 13 and 14, stage 2 andsubsequent analogous reaction, Example 15 was obtained:

¹H-NMR (DMSO-d₆): 1.15-1.68 (m, 8H); 1.92 (s, 6H); 2.52-2.70 (m, 2H);3.35-3.50 (m, 2H); 4.49 (m, 3H); 7.18-7.40 (m, 10 H).

¹³C-NMR (DMSO-d₆): 22.3; 23.7; 32.6; 32.7; 37.5; 58.1; 72.1; 72.7; 72.9;126.1 (br); 126.3 (br); 127.1 (br); 127.4; 128.1; 138.7; 139.7.

Only one diastereoisomer was isolated.

Example 162-(Cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol

By replacing phenol by cyclohexanol in Example 13 and 14, stage 2 andsubsequent analogous reaction, Example 16 was obtained:

¹H-NMR (DMSO-d₆): 1.10-1.57 (m, 16H); 1.80 (m, 2H); 1.92 (s, 6H); 2.63(br d, 2H, J=13.9 Hz); 3.22 (m, 1H); 3.28-3.45 (m, 3H); 4.31 (d, 1H,J=4.7 Hz); 7.23 (m, 1H); 7.28-7.35 (m, 4H).

¹³C-NMR (DMSO-d₆): 22.7; 23.2; 23.7; 25.3; 31.7; 32.6; 37.4; 58.3; 70.2;73.0; 76.4; 126.1; 126.5; 127.0; 139.6.

Only one diastereoisomer was isolated.

Example 172-Cyclohexyloxy-1-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)ethanol

In an analogous procedure to Example 16, replacing phenylmagnesiumchloride by 2-thienylmagnesium bromide in stage 6, Example 17 wasobtained analogously.

¹H-NMR (DMSO-d₆): 1.10-1.57 (m, 15H); 1.80 (m, 2H); 1.99 (s, 6H); 2.42(d, 2H, J=13.7 Hz); 3.21 (m, 1H); 3.27-3.44 (m, 3H); 4.34 (d, 1H, J=4.7Hz); 6.89 (dd, 1H, J=1.1 and 3.4 Hz); 7.02 (dd, 1H, J=3.4 and 5.1 Hz);7.37 (dd, 1H, J=1.1 and 5.1 Hz).

¹³C-NMR (DMSO-d₆): 22.2; 23.2; 23.6; 25.3; 31.7; 35.1; 37.3; 58.1; 70.1;72.9; 76.4; 122.8; 123.5; 126.0; 145.2.

Only one diastereoisomer was isolated.

Example 18 1-(4-Dimethylamino-4-phenylcyclohexyl)-2-indol-1-yl-ethanol

By replacing phenol by indole in Example 13 and 14, stage 2 andsubsequent analogous reaction, Example 18 was obtained:

¹H-NMR (CDCl₃): 1.44-1.64 (m, 3H); 1.64-1.90 (m, 4H); 2.05 (s, 6H);2.65-2.74 (m, 2H); 3.89 (ddd, 1H, J=2.8, 6.6, 9.2 Hz); 4.06 (dd, 1H,J=9.1, 14.3 Hz); 4.40 (dd, 1H, J=2.8, 14.3 Hz); 6.52 (d, 1H, J=3.1 Hz);7.11 (m, 1H); 7.18 (d, 1H, J=3.1 Hz); 7.22 (ddd, 1H, J=1.2, 7.1, 8.2Hz); 7.16-7.42 (m, 6H); 7.64 (d, 1H, J=7.9 Hz).

Example 191-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenylsulfanylethanol

By replacing phenol by thiophenol in Example 13 and 14, stage 2 andsubsequent analogous reaction, Example 19 was obtained:

¹H-NMR (CDCl₃): 1.48-1.64 (m, 4H); 1.66-1.82 (m, 4H); 2.10 (s, 6H);2.60-2.72 (m, 2H); 2.94 (dd, 1H, J=8.8 and 13.6 Hz); 3.29 (dd, 1H, J=3.4and 13.6 Hz) 3.64 (m, 1H); 7.21 (m, 1H); 7.25-7.43 (m, 9H).

LC-MS (method 8): [M+H]⁺: m/z=356.2, R_(t)=2.6 min.

Example 20 2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1-phenoxypropan-2-ol

Stage 7 was prepared analogously to Example 13 and 14, and starting fromthis the synthesis of Example 20 was carried out as described below:

Stage 8 1-(4-Dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanone

A 15% solution of Dess-Martin periodinane in methylene chloride (22.9 g,8.10 mmol) was added to a solution of1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol (800 mg, 2.35mmol) in anhydrous methylene chloride (25 ml). The mixture was stirredat room temperature for 4 h and then at 40° C. for 1.5 h and diethylether (100 ml) was then added. The suspension was washed with 25%potassium carbonate solution, 5% sodium bicarbonate solution, 1 M sodiumthiosulfate solution and water (50 ml of each). The organic phase wasdried with sodium sulfate and concentrated i. vac.

Yield: 931 mg (>100%), yellowish solid

¹H-NMR (DMSO-d₆): 1.40-1.53 (m, 2H); 1.62-1.72 (m, 2H); 1.75-1.88 (m,2H); 1.95 (s, 6H); 2.58-2.70 (m, 3H); 4.94 (s, 2H); 6.86-6.90 (m, 2H);6.91-6.96 (m, 1H); 7.25-7.30 (m, 3H); 7.33-7.37 (m, 4H).

Stage 9 2-(4-Dimethylamino-4-phenylcyclohexyl)-1-phenoxypropan-2-ol

A 3 M solution of methylmagnesium bromide in diethyl ether (8.8 ml, 26.7mmol) was added to a suspension of the product from stage 7 (crudeproduct, 300 mg, max. 0.89 mmol) in anhydrous tetrahydrofuran (30 ml),under argon and while cooling with ice, and the mixture was stirred atroom temperature for 3 h. Saturated ammonium chloride solution and water(10 ml of each) were then added dropwise to the mixture, while coolingwith ice, and the mixture was extracted with diethyl ether (3×20 ml).The combined organic phases were dried with sodium sulfate andconcentrated i. vac. The crude product (167 mg) was purified by flashchromatography (20 g, 20×2.0 cm) with ethyl acetate/methanol (9:1).

Yield: 102 mg (32%, based on stage 6), colourless oil

¹H-NMR (DMSO-d₆): 1.15 (s, 3H); 1.20-1.30 (m, 2H); 1.50-1.70 (m, 5H);1.92 (s, 6H); 2.71 (br, d, 2H, J=14.3 Hz); 3.76 (d, 1H, J=9.3 Hz); 3.83(d, 1H, J=9.3 Hz); 4.38 (s, 1H); 6.88-6.97 (m, 3H); 7.18-7.40 (m, 7H).

LC-MS (method 7): [M+H]⁺: m/z=354.3, R_(t)=3.3 min.

Comparison Example 13-{3-[4-(Dimethylamino)-4-phenylcyclohexyl]-3-hydroxyprop-1-ynyl}-1H-indole-1-carboxylicacid tert-butyl ester

The synthesis of this compound and the following data on the biologicalactivity are described in the literature (WO 04/043900)

Comparison Example 24-(Dimethylamino)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-2-yl)methanol

Stage 14-(Dimethylamino)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1′-pyrano[3,4-b]indol]-2-yl)methanol(One of 4 Possible Racemic Diastereoisomer Pairs)

2-(4-(Dimethylamino)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-2-yl)aceticacid methyl ester (190 mg, 0.44 mmol) was dissolved in a mixture of 2 NHCl (20 ml) and ethanol (20 ml) and the mixture was stirred at RT for 18h. For working up, the ethanol was stripped off in vacuo and the aqueousresidue was neutralized with NaHCO₃ and rendered strongly basic with 2 NNaOH. The aqueous solution was extracted with ethyl acetate (3×10 ml).The combined organic phases were dried over MgSO₄ and then concentrated.The solid residue obtained proved to be one of the four possiblediastereoisomers of the desired alcohol in the pure form. The productwas obtained in this way in a yield of 153 mg (89%) with a melting pointof 219-233° C. (from propan-2-ol).

¹³C-NMR (101 MHz, DMSO-d₆, δ ppm): 22.1, 27.9, 30.5, 31.0, 37.9, 43.9,59.1, 60.8, 61.6, 73.8, 106.5, 111.0, 117.3, 118.2, 120.4, 126.2, 126.3,127.59, 127.63, 135.9, 136.6, 137.4

Investigations of the Activity of the Compounds According to theInvention

Measurement of the ORL1 Binding

The compounds were investigated in a receptor binding assay with³H-nociceptin/orphanin FQ with membranes from recombinant CHO-ORL1cells. This test system was conducted in accordance with the methoddescribed by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824). Theconcentration of ³H-nociceptin/orphanin FQ in these experiments was 0.5nM. The binding assays were carried out with in each case 20 μg ofmembrane protein per 200 μl batch in 50 mM hepes, pH 7.4, 10 mM MgCl₂and 1 mM EDTA. The binding to the ORL1 receptor was determined using ineach case 1 mg of WGA-SPA beads (Amersham-Pharmacia, Freiburg) byincubation of the batch at RT for one hour and subsequent measurement ina Trilux scintillation counter (Wallac, Finland). The affinity is statedin Table 1 as the nanomolar K_(i) value in or % inhibition at c=1 μM.

Measurement of the μ Binding

The receptor affinity for the human μ opiate receptor was determined ina homogeneous setup in microtitre plates. For this, dilution series ofthe compound to be tested in each case were incubated with a receptormembrane preparation (15-40 μg of protein per 250 μl of incubationbatch) of CHO-K1 cells which express the human μ opiate receptor (RB-HOMreceptor membrane preparation from NEN, Zaventem, Belgium) in thepresence of 1 nmol/l of the radioactive ligand [³H]-naloxone (NET719,NEN, Zaventem, Belgium) and of 1 mg of WGA-SPA-Beads (wheat germagglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in atotal volume of 250 μl for 90 minutes at room temperature. 50 mmol/l ofTris-HCl supplemented with 0.05 wt. % of sodium azide and with 0.06 wt.% of bovine serum albumin was used as the incubation buffer. 25 μmol/lof naloxone were additionally added for determination of thenon-specific binding. After the end of the ninety-minute incubationtime, the microtitre plates were centrifuged for 20 minutes at 1,000 gand the radioactivity was measured in a β-counter (Microbeta-Trilux,PerkinElmer Wallac, Freiburg, Germany). The percentage displacement ofthe radioactive ligand from its binding to the human μ opiate receptorwas determined at a concentration of the test substances of 1 μmol/l andstated as the percentage inhibition (% inhibition) of the specificbinding. Starting from the percentage displacement by variousconcentrations of the substances of the general formula I to be tested,IC₅₀ inhibitory concentrations which cause a 50 percent displacement ofthe radioactive ligand were calculated in some cases. By conversion bymeans of the Cheng-Prusoff relationship, K_(i) values for the testsubstances were obtained. In some cases determination of the K_(i) valuewas dispensed with and only the inhibition at a test concentration of 1μM was determined.

Testing of Analgesia in the Tail Flick Test in Rats

The analgesic activity of the test compounds of Example 3 wasinvestigated in the focal ray (tail flick) test in rats in accordancewith the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79(1941)). Female Sprague-Dawley weighing between 134 and 189 g were usedfor this. The animals were placed individually in special test cages andthe base of the tail was exposed to a focused heat ray of a lamp(Tail-flick type 50/08/1.bc, Labtec, Dr Hess). The intensity of the lampwas adjusted such that in the case of untreated animals the time betweenswitching on of the lamp to sudden pulling away of the tail (painlatency) was 2.5-5 seconds. Before administration of a test compound,the animals were pretested twice in the course of 30 minutes and themean of these measurements was calculated as the pretest mean The painwas measured 20, 40 and 60 min after intravenous administration. Theanalgesic action was determined as the increase in pain latency (% MPE)according to the following formula:[(T₁−T₀)/(T₂−T₀)]×100

In this formula, T₀ is the latency period before and T₁ the latencyperiod after administration of the substance, T₂ is the maximum exposuretime (12 sec).

To determine the dose dependency, the particular test compound wasadministered in 3-5 logarithmically increasing doses, which included thethreshold and the maximum active dose in each case, and the ED₅₀ valueswere determined with the aid of regression analysis. The ED₅₀calculation was performed at the action maximum, 20 minutes afterintravenous administration of the substance.

Nephelometric Solubility Study (Phosphate Buffer pH 7.4)

This method investigates the solubility of a substance at fixedconcentrations (1 μM, 3 μM, 10 μM, 30 μM and 100 μM) in 10 mM phosphatebuffer solution at pH 7.4. A 10 mM solution of the substances in DMSO isinitially required, from which 100-fold stock solutions of theabovementioned concentration levels are prepared, again in DMSO, thefinal DMSO concentration in the test batch being 1% (v/v). Theexperiment is carried out in a multiple determination. After addition ofthe DMSO stock solutions to the buffer, the batch is incubated at 37° C.for 2 h, before a determination of the absorption at 620 nm takes place.If the absorption of the samples rises above that of the purebuffer/DMSO solution, this is an indicator of formation of aprecipitate. The lower solubility limit (“lower boundary”) is theconcentration which precedes that with the first formation of aprecipitate (e.g. 3 μM, if formation of a precipitate was detected at 10μM).

Comparison Studies

% Ki % Ki TF rat Solu- inhibition (ORL1) inhibition (μ) ED₅₀ bility(ORL1) mean (μ) mean i.v. (pH 7) [1 μM] [nm] [1 μM] [nm] [μg/kg][μmol/l] Example 1 93 99 Example 3 1.9 3.2 31.7 Example 4 605 2075 100Example 5 97 103 Example 6 0.76 1.3 Example 7 0.94 1.8 Example 8 400 11Example 9 370 11.3 Example 12 71 99 Example 13 30 6.5 Example 15 13010.7 Example 16 91 12 Example 17 45 4.6 Example 18 4.1 1.0 Comparison 1730 86 Comparison 2 80 99 10

It can be seen from the present table that compared with the similarstructure of the known compound of Comparison Example 1, the compoundsaccording to the invention of Examples 1, 3, 4, 5, 6, 7, 8, 9, 12, 13,15, 16, 17 and 18 show a surprisingly high binding to the ORL1 receptorand sometimes additionally also to the μ opioid receptor. It canfurthermore be seen that the compound according to the inventionaccording to Example 4 has an about 10-fold better solubility in aqueousmedia than the compound of Comparison Example 2.

1. A compound of the formula (1):

wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independentlyof each other are chosen from the group consisting of —H, —F, —Cl, —Br,—I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,—OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —S(═O)₁₋₂R₀,—S(═O)₁₋₂OH, —S(═O)₁₋₂OR₀, —S(═O)₁₋₂NH₂, —S(═O)₁₋₂NHR₀ or—S(═O)₁₋₂N(R₀)₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, and —NHC(═O)N(R₀)₂; or Y₁ andY₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ together represent ═O;R₀ in each case independently represents —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,—C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic,—C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; R₁ and R₂independently of each other represent —H or —C₁₋₈-aliphatic; or R₁ andR₂ together form a ring and represent —(CH₂)₂₋₄—; R₃ represents —R₀; R₄represents —H, —F, —Cl, —Br, —I, —R₀, —C(═O)H, —C(═O)OR₀, —CN,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,—OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,—N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NHR₀, —NHC(═O)—N(R₀)₂,—NO₂, —SH, —SR₀, —S(═O)₁₋₂R₀, —S(═O)₁₋₂OH, —S(═O)₁₋₂OR₀, —S(═O)₁₋₂NH₂,—S(═O)₁₋₂NHR₀, —S(═O)₁₋₂N(R₀)₂, —OS(═O)₁₋₂R₀, —OS(═O)₁₋₂OH,—OS(═O)₁₋₂OR₀, —OS(═O)₁₋₂NH₂, —OS(═O)₁₋₂NHR₀ or —OS(═O)₁₋₂N(R₀)₂; R₅represents —H, —R₀, —C(═O)H, —C(═O)R₀, —C(═O)OR₀, —CN, —C(═O)NH₂,—C(═O)NHR₀ or —C(═O)N(R₀)₂; wherein “aliphatic” in each case is abranched or unbranched, saturated or mono- or polyunsaturated,unsubstituted or mono- or polysubstituted, aliphatic hydrocarbonradical; “cycloaliphatic” in each case is a saturated or mono- orpolyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic,mono- or multicyclic hydrocarbon radical; wherein with respect to“aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” issubstitution once or several times by substituents chosen independentlyof each other from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂,—CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂,—C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,—OC(═O)NHR₀,—OC(═O)—N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)—NHR₀, -—NH—C(═O)N(R₀)₂, —Si(R₀)₃ and—PO(OR₀)₂; “aryl” in each case independently represents a carbocyclicring system having at least one aromatic ring, but without hetero atomsin this ring, wherein the aryl radicals can optionally be fused withfurther saturated, (partially) unsaturated or aromatic ring systems,which in their turn can have one or more hetero ring atoms, in each caseindependently of each other chosen from N, O and S, and wherein eacharyl radical can be unsubstituted or mono- or polysubstituted, whereinthe substituents on aryl can be identical or different and can be in anydesired and possible position of the aryl; “heteroaryl” represents a 5-,6- or 7-membered cyclic aromatic radical which contains 1, 2, 3, 4 or 5hetero atoms, wherein the hetero atoms are identical or different andare nitrogen, oxygen or sulfur and the heteroaryl can be unsubstitutedor mono- or polysubstituted; wherein in the case of substitution on theheteroaryl the substituents can be identical or different and can be inany desired and possible position of the heteroaryl; and wherein theheterocyclyl can also be part of a bi- or polycyclic system; whereinwith respect to “aryl” and “heteroaryl”, “mono- or polysubstituted” issubstitution once or several times of the ring system by substituentschosen from the group consisting of —F, Cl, —Br, —I, —CN, —NO₂, —CHO,═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,—OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃ and—PO(OR₀)₂; wherein N ring atoms optionally present can in each case beoxidized; in the form of an individual stereoisomer or mixture thereof,a free compound and/or a physiologically acceptable salt and/or solvatethereof.
 2. Compound according to claim 1, wherein R₄ represents —H, —F,—Cl, —Br, —I, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl,—C₃₋₈-cycloaliphatic-heteroaryl, —C(═O)H, —C(═O)R₀, —C(═O)OR₀, —CN,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,—OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,—N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NHR₀, —NHC(═O)—N(R₀)₂,—NO₂, —SH, —SR₀, —S(═O)₁₋₂R₀, —S(═O)₁₋₂OH, —S(═O)₁₋₂OR₀, —S(═O)₁₋₂NH₂,—S(═O)₁₋₂NHR₀, —S(═O)₁₋₂N(R₀)₂, —OS(═O)₁₋₂R₀, —OS(═O)₁₋₂OH,OS(═O)₁₋₂OR₀, —OS(═O)₁₋₂NH₂, —OS(═O)₁₋₂NHR₀ or —OS(═O)₁₋₂N(R₀)₂. 3.Compound according to claim 1, wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ andY₄′ in each case represent —H.
 4. Compound according to claim 1, whereinR₃ is chosen from the group consisting of -phenyl, -benzyl or-phenethyl, in each case unsubstituted or mono- or polysubstituted onthe ring; —C₁₋₅-aliphatic, —C₄₋₆-cycloaliphatic, -pyridyl, -thienyl,-thiazolyl, -imidazolyl, -1,2,4-triazolyl and -benzimidazolyl, in eachcase unsubstituted or mono- or polysubstituted.
 5. Compound according toclaim 1, wherein R₅ represents —H.
 6. Compound according to claim 1,which has the formula (4), (5), (6), (7), (8) or (9):

wherein, if present, R_(A) represents —H, —F, —Cl, —CN, —NO₂ or —OCH₃;and (Hetero-)aryl represents heteroaryl or aryl, in each caseunsubstituted or mono- or polysubstituted.
 7. Compound according toclaim 1, chosen from the group consisting of1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenylethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenoxyethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(1H-indol-1-yl)ethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(isoindolin-2-yl)ethanol,1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(4-fluorophenyl)ethanol;1-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-phenylethanol;1-(4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-2-phenylethanol;1-(4-(dimethylamino)-4-(thiophen-2-yl)cyclohexyl)-2-phenylethanol;1-(4-butyl-4-(dimethylamino)cyclohexyl)-2-phenylethanol;1-cyclopentyl-2-(4-(dimethylamino)-4-phenylcyclohexyl)-3-phenylpropan-2-ol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-2-(pyridin-4-yl)ethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylthio)ethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylsulfonyl)ethanol;2-(cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;2-(benzyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenethoxyethanol;2-((1H-indol-3-yl)methoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;2-(2-(1H-indol-3-yl)ethoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-((2-(triethylsilyl)-1H-indol-3-yl)-methoxy)ethanol;1-(2-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-hydroxyethyl)piperidin-2-one;2-(4,4a-dihydro-1H-pyrido[3,4-b]indol-2(3H,9H,9aH)-yl)-1-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)ethanol;1-cinnamoyl-3-(2-(4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one;2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenylpropan-2-ol;2-(4-(dimethylamino)-4-phenylcyclohexyl)-1,3-diphenylpropan-2-ol;2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-2-yl)propan-2-ol;2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-3-yl)propan-2-ol;and2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-4-yl)propan-2-ol;or a physiologically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound according to claim 1 in the form of an individualstereoisomer or mixture thereof, a free compound and/or aphysiologically acceptable salt thereof, and optionally one or moresuitable additives and/or auxiliary substances and/or optionally furtheractive compounds.
 9. A method of treating pain in a patient in need ofsuch treatment, said method comprising administering to said patient aneffective amount therefor of a compound according to claim 1 in the formof an individual stereoisomer or mixture thereof, a free compound and/ora physiologically acceptable salt thereof.
 10. A method for treating acondition selected from the group consisting of anxiety states, ofstress and syndromes associated with stress, depression, epilepsy,Alzheimer's disease, senile dementia, general cognitive dysfunctions,learning and memory disorders (as a nootropic), withdrawal symptoms,alcohol and/or drug and/or medicament abuse and/or dependency, sexualdysfunctions, cardiovascular diseases, hypotension, hypertension,tinnitus, pruritus, migraine, impaired hearing, lack of intestinalmotility, impaired food intake, anorexia, obesity, locomotor disorders,diarrhoea, cachexia, urinary incontinence or as a muscle relaxant,anticonvulsive or anaesthetic or for co-administration in treatment withan opioid analgesic or with an anaesthetic, for diuresis orantinatriuresis, anxiolysis, for modulation of motor activity, formodulation of neurotransmitter secretion and treatment ofneurodegenerative diseases associated therewith, for treatment ofwithdrawal symptoms and/or for reduction of the addiction potential ofopioids, said method comprising administering to a patient in need ofsuch treatment an effective amount therefor of a compound according toclaim 1 in the form of an individual stereoisomer or mixture thereof, afree compound and/or a physiologically acceptable salt and/or solvatethereof.